Amide derivatives bearing a cyclopropylaminoacarbonyl substituent useful as cytokine inhibitors

ABSTRACT

The invention concerns a compound of the Formula (I), wherein Qa is heteroaryl and is substituted with halogeno; R1 and R2 are hydrogen; and Qb is phenyl or heteroaryl, and Qb may optionally bear 1 or 2 substituents selected from hydroxy, halogeno and (1-6C)alkyl, or a pharmaceutically-acceptable salt thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/080,583, filed Apr. 5, 2011, which is a continuation of U.S.application Ser. No. 10/581,305, filed Oct. 12, 2006, which is a U.S.national phase under 35 U.S.C. §371 of International application serialno. PCT/GB2004/005241, filed Dec. 15, 2004, which claims the benefit ofUnited Kingdom application serial no. 0329572.2, filed Dec. 20, 2003,the disclosures of each are incorporated herein by reference in theirentirety.

This invention relates to amide derivatives, orpharmaceutically-acceptable salts thereof, which are useful asinhibitors of cytokine mediated disease. The invention also relates toprocesses for the manufacture of said amide derivatives, topharmaceutical compositions containing said amide derivatives and totheir use in therapeutic methods, for example by virtue of inhibition ofcytokine mediated disease.

The amide derivatives disclosed in the present invention are inhibitorsof the production of cytokines such as Tumour Necrosis Factor(hereinafter TNF), for example TNFα, and various members of theinterleukin (hereinafter IL) family, for example IL-1, IL-6 and IL-8.Accordingly the amide derivatives of the invention will be useful in thetreatment of diseases or medical conditions in which excessiveproduction of cytokines occurs, for example excessive production of TNFαor IL-1. It is known that cytokines are produced by a wide variety ofcells such as monocytes and macrophages and that they give rise to avariety of physiological effects which are believed to be important indisease or medical conditions such as inflammation and immunoregulation.For example, TNFα and IL-1 have been implicated in the cell signallingcascade which is believed to contribute to the pathology of diseasestates such as inflammatory and allergic diseases and cytokine-inducedtoxicity. It is also known that, in certain cellular systems, TNFαproduction precedes and mediates the production of other cytokines suchas IL-1.

Abnormal levels of cytokines have also been implicated in, for example,the production of physiologically-active eicosanoids such as theprostaglandins and leukotrienes, the stimulation of the release ofproteolytic enzymes such as collagenase, the activation of the immunesystem, for example by stimulation of T-helper cells, the activation ofosteoclast activity leading to the resorption of calcium, thestimulation of the release of proteoglycans from, for example,cartilage, the stimulation of cell proliferation and to angiogenesis.

Cytokines are also believed to be implicated in the production anddevelopment of disease states such as inflammatory and allergicdiseases, for example inflammation of the joints (especially rheumatoidarthritis, osteoarthritis and gout), inflammation of thegastrointestinal tract (especially inflammatory bowel disease,ulcerative colitis, Crohn's disease and gastritis), skin disease(especially psoriasis, eczema and dermatitis) and respiratory disease(especially asthma, bronchitis, allergic rhinitis, chronic obstructivepulmonary disease and adult respiratory distress syndrome), and in theproduction and development of various cardiovascular and cerebrovasculardisorders such as congestive heart failure, acute heart failure,myocardial infarction, the formation of atherosclerotic plaques,hypertension, platelet aggregation, angina, stroke, reperfusion injury,vascular injury including restenosis and peripheral vascular disease,and, for example, various disorders of bone metabolism such asosteoporosis (including senile and postmenopausal osteoporosis), Paget'sdisease, bone metastases, hypercalcaemia, hyperparathyroidism,osteosclerosis, osteoperosis and periodontitis, and the abnormal changesin bone metabolism which may accompany rheumatoid arthritis andosteoarthritis. Excessive cytokine production has also been implicatedin mediating certain complications of bacterial, fungal and/or viralinfections such as endotoxic shock, septic shock and toxic shocksyndrome and in mediating certain complications of CNS surgery or injurysuch as neurotrauma and ischaemic stroke. Excessive cytokine productionhas also been implicated in mediating or exacerbating the development ofdiseases involving cartilage or muscle resorption, pulmonary fibrosis,cirrhosis, renal fibrosis, the cachexia found in certain chronicdiseases such as malignant disease and acquired immune deficiencysyndrome (AIDS), chronic obstructive pulmonary disease, tumourinvasiveness and tumour metastasis and multiple sclerosis. Excessivecytokine production has also been implicated in pain.

Evidence of the central role played by TNFα in the cell signallingcascade which gives rise to rheumatoid arthritis is provided by theefficacy in clinical studies of antibodies of TNFα (The Lancet, 1994,344, 1125 and British Journal of Rheumatology, 1995, 34, 334).

Thus cytokines such as TNFα and IL-1 are believed to be importantmediators of a considerable range of diseases and medical conditions.Accordingly it is expected that inhibition of the production of and/oreffects of these cytokines will be of benefit in the prophylaxis,control or treatment of such diseases and medical conditions.

Without wishing to imply that the amide derivatives disclosed in thepresent invention possesses pharmacological activity only by virtue ofan effect on a single biological process, it is believed that the amidederivatives inhibit the effects of cytokines by virtue of inhibition ofthe enzyme p38 kinase. p38 kinase, otherwise known as cytokinesuppressive binding protein (hereinafter CSBP) and reactivating kinase(hereinafter RK), is a member of the mitogen-activated protein(hereinafter MAP) kinase family of enzymes which is known to beactivated by physiological stress such as that induced by ionisingradiation, cytotoxic agents, and toxins, for example endotoxins such asbacterial lipopolysaccharide, and by a variety of agents such as thecytokines, for example TNFα and IL-1. It is known that p38 kinasephosphorylates certain intracellular proteins which are involved in thecascade of enzymatic steps which leads to the biosynthesis and excretionof cytokines such as TNFα and IL-1. Known inhibitors of p38 kinase havebeen reviewed in Exp. Onin. Ther. Patents, 2000, 10(1), 25-37. p38kinase is known to exist in isoforms identified as p38α and p38β.

The amide derivatives disclosed in the present invention are inhibitorsof the production of cytokines such as TNF, in particular of TNFα, andvarious interleukins, in particular IL-1.

It is known from the International Patent Application WO 00/07980 thatcertain amide derivatives are inhibitors of the production of cytokinessuch as TNF, and various interleukins. One of the disclosed compounds isN-cyclobutyl-3-(3,4-dimethoxybenzamido)-4-methylbenzamide (ComparatorCompound X).

There is no disclosure in this document of an amide derivative whichbears a cyclopropylaminocarbonyl substituent at the 3-position of thecentral 6-methylphenyl core. We have now found that such compoundspossess potent cytokine inhibitory activity and have desirable activityprofiles.

Subsequently, International Patent Application WO 2004/071440 hasdisclosed amide derivatives that bear a cycloalkylaminocarbonylsubstituent at the 3-position of the central 6-methylphenyl core.However, this application discloses thiazolyl-based compounds, whereinthe thiazole ring is mainly substituted with a substituted amino group.

According to the present invention there is provided a compound of theFormula I

whereinQ_(a) is phenyl or heteroaryl, and Q_(a) may optionally bear 1 or 2substituents selected from hydroxy, halogeno, trifluoromethyl, cyano,amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl;R₁ and R₂ are each independently selected from hydrogen, (1-6C)alkyl,(2-6C)alkenyl and (2-6C)alkynyl; andQ_(b) is phenyl, heteroaryl or heterocyclyl, and Q_(b) may optionallybear 1 or 2 substituents selected from hydroxy, halogen, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, aminosulphonyl,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl and(3-6C)cycloalkylsulphonyl;and wherein any of the substituents on Q_(a) or Q_(b) definedhereinbefore which comprise a CH₂ group which is attached to 2 carbonatoms or a CH₃ group which is attached to a carbon atom may optionallybear on each said CH₂ or CH₃ group one or more substituents selectedfrom hydroxy, cyano, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylaminoand di-[(1-6C)alkyl]amino;or a pharmaceutically-acceptable salt thereof.

According to a further aspect of present invention there is provided acompound of the Formula I wherein

Q_(a) is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, andQ_(a) may optionally bear 1 or 2 substituents selected from halogeno,(1-6C)alkyl and (1-6C)alkoxy;

R₁ and R₂ are each independently selected from hydrogen, (1-6C)alkyl,(2-6C)alkenyl and (2-6C)alkynyl; and

Q_(b) is phenyl, heteroaryl or heterocyclyl, and Q_(b) may optionallybear 1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, aminosulphonyl,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl and(3-6C)cycloalkylsulphonyl;and wherein any of the substituents on Q_(a) or Q_(b) definedhereinbefore which comprise a CH₂ group which is attached to 2 carbonatoms or a CH₃ group which is attached to a carbon atom may optionallybear on each said CH₂ or CH₃ group one or more substituents selectedfrom hydroxy, cyano, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylaminoand di-[(1-6C)alkyl]amino;or a pharmaceutically-acceptable salt thereof.

In this specification, the term (1-6C)alkyl includes straight-chain andbranched-chain alkyl groups such as propyl, isopropyl and tert-butyl.References to individual alkyl groups such as “propyl” are specific forthe straight-chain version only, references to individual branched-chainalkyl groups such as “isopropyl” are specific for the branched-chainversion only. In this specification, the term (3-6C)cycloalkoxy includescyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.References to individual cycloalkyl groups such as “cyclopentyl” arespecific for that 5-membered ring only.

It is to be understood that, insofar as certain of the compounds ofFormula I defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the property of inhibiting cytokines, in particular TNF. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, inhibitory properties against TNF may beevaluated using the standard laboratory techniques referred tohereinafter.

Suitable values for the generic radicals referred to above include thoseset out below.

A suitable value for Q_(a) or Q_(b) when it is heteroaryl is, forexample, an aromatic 5- or 6-membered monocyclic ring, a 9- or10-membered bicyclic ring or a 13- or 14-membered tricyclic ring eachwith up to five ring heteroatoms selected from oxygen, nitrogen andsulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl,benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl,quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl,naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl,S,S-dioxodibenzothiophenyl, xanthenyl, dibenzo-1,4-dioxinyl,phenoxathiinyl, phenoxazinyl, dibenzothiinyl, phenothiazinyl,thianthrenyl, benzofuropyridyl, pyridoindolyl, acridinyl orphenanthridinyl, preferably furyl, thienyl, oxazolyl, isoxazolyl,imidazolyl, pyrido[1,2-a]imidazolyl, pyrazolyl, thiadiazolyl,isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, morepreferably furyl, isoxazolyl, thiazolyl, pyrido[1,2-a]imidazolyl,thiadiazolyl or pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

A suitable value for Q_(b) when it is heterocyclyl is, for example, anon-aromatic saturated or partially saturated 3- to 10-memberedmonocyclic or bicyclic ring or a 5- to 7-membered monocyclic ring eachwith up to five heteroatoms selected from oxygen, nitrogen and sulphur,for example oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, 1,1-dioxidoisothiazolidinyl,morpholinyl, thiomorpholinyl, tetrahydro-1,4-thiazinyl,1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl or tetrahydropyrimidinyl or benzo derivatives thereofsuch as 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indolinyl,isoindolinyl, chromanyl and isochromanyl, preferably azetidin-1-yl,3-pyrrolin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,1,1-dioxidoisothiazolidin-2-yl, morpholino,1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidin-3-yl, piperidin-4-yl,homopiperidin-1-yl, piperidino, piperazin-1-yl or homopiperazin-1-yl. Asuitable value for such a group which bears 1 or 2 oxo or thioxosubstituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.

Suitable values for various substituents on Q_(a) or Q_(b) or for R₁ andR₂ include:—

for halogeno: fluoro, chloro, bromo and iodo; for (1-6C)alkyl: methyl,ethyl, propyl, isopropyl and tert-butyl; for (2-6C)alkenyl: vinyl andallyl; for (2-6C)alkynyl: ethynyl and 2-propynyl; for (1-6C)alkoxy:methoxy, ethoxy, propoxy, isopropoxy and butoxy; for(1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyland tert-butoxycarbonyl; for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl,N-ethylcarbamoyl and N-propylcarbamoyl; forN,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl; for (2-6C)alkanoyl:acetyl and propionyl; for (1-6C)alkylamino: methylamino, ethylamino andpropylamino; for di-[(1-6C)alkyl]amino: dimethylamino, diethylamino andN-ethyl-N-methylamino; for halogeno-(1-6C)alkyl: fluoromethyl,chloromethyl, bromomethyl, difluoromethyl, dichloromethyl,dibromomethyl, 2-fluoroethyl, 2-chloroethyl and 2-bromoethyl; forhydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and3-hydroxypropyl; for (1-6C)alkoxy-(1-6C)alkyl: methoxymethyl,ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and3-methoxypropyl; for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl,1-cyanoethyl and 3-cyanopropyl; for amino-(1-6C)alkyl: aminomethyl,2-aminoethyl, 1-aminoethyl and 3-aminopropyl; for (1-6C)alkylamino-methylaminomethyl, ethylaminomethyl, (1-6C)alkyl: 1-methylaminoethyl,2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl; fordi-[(1-6C)alkyl]amino- dimethylaminomethyl, diethylaminomethyl,(1-6C)alkyl: 1-dimethylaminoethyl, 2-dimethylaminoethyl and3-dimethylaminopropyl. for (2-6C)alkanoyloxy: acetoxy and propionyloxy:for (1-6C)alkanoylamino: formamido, acetamido and propionamido; forcarboxy-(1-6C)alkyl: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl,3-carboxypropyl and 4-carboxybutyl; for (1-6C)alkoxycarbonyl-methoxycarbonylmethyl, ethoxycarbonylmethyl, (1-6C)alkyl:tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl,1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl,3-methoxycarbonylpropyl and 3-ethoxycarbonylpropyl; for (1-6C)alkylthio:methylthio, ethylthio and propylthio; for (1-6C)alkylsulphinyl:methylsulphinyl, ethylsulphinyl and propylsulphinyl; for(1-6C)alkylsulphonyl: methylsulphonyl, ethylsulphonyl andpropylsulphonyl; for N-(1-6C)allcylsulphamoyl: N-methylsulphamoyl andN-ethylsulphamoyl; for N,N-di-[(1-6C)alkyl]sulphamoyl:N,N-dimethylsulphamoyl;

A suitable value for a substituent on Q_(b) when it is (3-6C)cycloalkylis, for example, a saturated monocyclic 3- to 6-membered carbon ringsuch as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferablycyclopropyl, cyclopentyl or cyclohexyl, more preferably cyclopropyl.

A suitable value for a substituent on Q_(b) when it is(3-6C)cycloalkyl-(1-6C)alkyl is, for example, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl,preferably cyclopropylmethyl or cyclopropylethyl, more preferablycyclopropylmethyl.

A suitable pharmaceutically-acceptable salt of a compound of the FormulaI, for example, an acid-addition salt of a compound of the Formula Iwhich is sufficiently basic, for example, an acid-addition salt with aninorganic or organic acid such as hydrochloric, hydrobromic, sulphuric,phosphoric, trifluoroacetic, citric, maleic, tartaric, fumaric,hemifumaric, succinic, hemisuccinic, mandelic, methanesulphonic,dimethanesulphonic, ethane-1,2-sulphonic, benzenesulphonic, salicylic or4-toluenesulphonic acid.

Further values of Q_(a), Q_(b), R₁ and R₂ are as follows. Such valuesmay be used where appropriate with any of the definitions, claims orembodiments defined hereinbefore or hereinafter.

Q_(a) is phenyl or heteroaryl, and Q_(a) may optionally bear 1 or 2substituents selected from hydroxy, halogen, trifluoromethyl, cyano,amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl.

Q_(a) is heteroaryl, and Q_(a) may optionally bear 1 or 2 substituentsselected from hydroxy, halogeno, trifluoromethyl, cyano, amino,(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl.

Q_(a) is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, andQ_(a) may optionally bear 1 or 2 substituents selected from hydroxy,halogeno, trifluoromethyl, cyano, amino, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and(1-6C)alkoxycarbonyl.

Q_(a) is phenyl or heteroaryl, and Q_(a) may optionally bear 1 or 2substituents selected from, halogeno, (1-6C)alkyl and (1-6C)alkoxy.

Q_(a) is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, andQ_(a) may optionally bear 1 or 2 substituents selected from hydroxy,halogeno, (1-6C)alkyl and (1-6C)alkoxy.

Q_(a) is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, andQ_(a) may optionally bear 1 or 2 substituents selected from halogeno,(1-6C)alkyl and (1-6C)alkoxy.

Q_(a) is phenyl, pyridyl or pyrimidinyl, and Q_(a) may optionally bear 1or 2 substituents selected from halogeno, (1-6C)alkyl and (1-6C)alkoxy.

Q_(a) is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, andQ_(a) may optionally bear 1 or 2 substituents selected from hydroxy andhalogeno.

Q_(a) is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, andQ_(a) may optionally bear 1 or 2 substituents selected from hydroxy,chloro and fluoro.

Q_(a) is phenyl, and Q_(a) may optionally bear 1 or 2 substituentsselected from hydroxy, chloro and fluoro.

Q_(a) is phenyl, and Q_(a) may optionally bear 1 or 2 fluorosubstituents.

Q_(a) is phenyl which optionally bears 1 or 2 substituents selected fromhalogeno, (1-6C)alkyl and (1-6C)alkoxy.

Q_(a) is heteroaryl, which optionally bears 1 or 2 substituents selectedfrom halogeno, (1-6C)alkyl and (1-6C)alkoxy.

Q_(a) is phenyl or heteroaryl, and Q_(a) may optionally bear 1 or 2substituents selected from fluoro, chloro, methyl and methoxy.

Q_(a) is phenyl, which optionally bears 1 or 2 substituents selectedfrom fluoro, chloro, methyl and methoxy.

Q_(a) is heteroaryl, which optionally bears 1 or 2 substituents selectedfrom fluoro, chloro, methyl and methoxy.

Q_(a) is phenyl, pyridyl or pyrimidinyl, which bears 1 or 2 substituentsselected from fluoro, chloro, methyl and methoxy.

Q_(a) is phenyl or heteroaryl, which bears 1 or 2 substituents selectedfrom fluoro, chloro, methyl and methoxy.

Q_(b) is phenyl, heteroaryl or heterocyclyl, and Q_(b) may optionallybear 1 or 2 substituents selected from hydroxy, halogen, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl.

Q_(b) is phenyl or heteroaryl, and Q_(b) may optionally bear 1 or 2substituents selected from hydroxy, halogen, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl,(1-6C)alkoxy, (3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,aminosulphonyl, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyland (3-6C)cycloalkylsulphonyl;

and wherein any of the substituents on Q_(b) which comprise a CH₂ groupwhich, is attached to 2 carbon atoms or a CH₃ group which is attached toa carbon atom may optionally bear on each said CH₂ or CH₃ group one ormore substituents selected from hydroxy, cyano, amino, (1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino.

Q_(b) is phenyl or heteroaryl, and Q_(b) may optionally bear 1 or 2substituents selected from hydroxy, halogeno, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl.

Q_(b) is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,thiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, oxazolyl, furanyl,thienyl, benzimidazolyl, isoquinolinyl, quinolinyl, benzothiazolyl orpyrido[1,2-a]imidazolyl, and Q_(b) may optionally bear 1 or 2substituents selected from hydroxy, halogen, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl,(1-6C)alkoxy, (3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,aminosulphonyl, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyland (3-6C)cycloalkylsulphonyl;

and wherein any of the substituents on Q_(b) which comprise a CH₂ groupwhich is attached to 2 carbon atoms or a CH₃ group which is attached toa carbon atom may optionally bear on each said CH₂ or CH₃ group one ormore substituents selected from hydroxy, cyano, amino, (1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino.

Q_(b) is phenyl, pyridyl, thiazolyl, furanyl, pyrido[1,2-a]imidazolyl,thiadiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperizinyl orpyrroldinyl, and Q_(b) may optionally bear 1 or 2 substituents selectedfrom hydroxy, halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,(3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl.

Q_(b) is phenyl, pyridyl, thiazolyl, furanyl, pyrido[1,2-a]imidazolyl,thiadiazolyl, oxazolyl or isoxazolyl, and Q_(b) may optionally bear 1 or2 substituents selected from hydroxy, halogeno, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl.

Q_(b) is phenyl, pyridyl, thiazolyl, furanyl, pyrido[1,2-a]imidazolyl,thiadiazolyl, oxazolyl or isoxazolyl, and Q_(b) may optionally bear 1 or2 substituents selected from hydroxy, fluoro, chloro, methyl, ethyl,isopropyl, methoxy, ethoxy, methoxycarbonyl and ethoxycarboyl.

R₁ and R₂ are each independently selected from hydrogen, (1-6C)alkyl,(2-6C)alkenyl and (2-6C)alkynyl;

R₁ and R₂ are each independently selected from hydrogen and (1-6C)alkyl.

R₁ and R₂ are hydrogen.

Particular novel compounds of the invention include, for example, amidederivatives of the Formula I, or pharmaceutically-acceptable saltsthereof, wherein:—

(a) Q_(a) is phenyl or heteroaryl, and Q_(a) may optionally bear 1 or 2substituents selected from hydroxy, halogeno, trifluoromethyl, cyano,amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl;Q_(b) is phenyl, heteroaryl or heterocyclyl, and Q_(b) may optionallybear 1 or 2 substituents selected from hydroxy, halogen, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,hydroxy(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl and R₁ and R₂ are hydrogen.(b) Q_(a) is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, andQ_(a) may optionally bear 1 or 2 substituents selected from hydroxy,halogeno, trifluoromethyl, cyano, amino, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and(1-6C)alkoxycarbonyl;Q_(b) is phenyl, pyridyl, thiazolyl, furanyl, pyrido[1,2-a]imidazolyl,thiadiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperizinyl orpyrroldinyl, and Q_(b) may optionally bear 1 or 2 substituents selectedfrom hydroxy, halogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,(3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl andR₁ and R₂ are hydrogen.(c) Q_(a) is phenyl which optionally bears 1 or 2 substituents selectedfrom, halogeno, (1-6C)alkyl and (1-6C)alkoxy; Q_(b) is phenyl, pyridyl,thiazolyl, furanyl, Pyrido[1,2-a]imidazolyl, thiadiazolyl, oxazolyl orisoxazolyl, and Q_(b) may optionally bear 1 or 2 substituents selectedfrom hydroxy, halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,(3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl andR₁ and R₂ are hydrogen.(d) Q_(a) is phenyl, which optionally bears 1 or 2 substituents selectedfrom, fluoro, chloro, methyl and methoxy; Q_(b) is phenyl, pyridyl,thiazolyl, furanyl, pyrido[1,2-a]imidazolyl, thiadiazolyl, oxazolyl orisoxazolyl, and Q_(b) may optionally bear 1 or 2 substituents selectedfrom hydroxy, fluoro, chloro, methyl, ethyl, isopropyl, methoxy, ethoxy,methoxycarbonyl and ethoxycarbonyl and R₁ and R₂ are hydrogen.

A particular preferred compound of the invention is, for example:—

-   3-{[4-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide;-   3-{[3-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide;-   4-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methylbenzamide;-   4-(benzyloxy)-3-fluoro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}benzamide;-   4-(benzyloxy)-3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}benzamide;-   N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide;-   N-cyclopropyl-4-methyl-3-{[4-(1,3-thiazol-4-ylmethoxy)benzoyl]amino}benzamide;-   N-cyclopropyl-4-methyl-3-{[4-(pyridin-3-ylmethoxy)benzoyl]amino}benzamide;-   N-cyclopropyl-4-methyl-3-{4-[(5-methyl    isoxazol-3-yl)methoxy]benzoyl}amino)benzamide;-   3-({4-[(5-chloro-1,2,3-thiadiazol-4-yl)methoxy]benzoyl}amino)-N-cyclopropyl-4-methylbenzamide;-   N-cyclopropyl-3-{[4-(imidazo[1,2-a]pyridin-2-ylmethoxy)benzoyl]amino}-4-methylbenzamide;-   N-cyclopropyl-4-methyl-3-({4-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzoyl}amino)benzamide;-   N-cyclopropyl-3-({4-[(3,5-dimethylisoxazol-4-yl)methoxy]benzoyl}amino)-4-methylbenzamide;-   N-cyclopropyl-4-methyl-3-{[4-(1,2,5-thiadiazol-3-ylmethoxy)benzoyl]amino}benzamide;-   methyl    5-({-4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}methyl)-2-furoate;-   3-({4-[(2-chloro-1,3-thiazol-5-yl)methoxy]benzoyl}amino)-N-cyclopropyl-4-methylbenzamide;-   4-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methoxybenzamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methoxy-4-(pyridin-2-ylmethoxy)benzamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methoxy-4-(1,3-thiazol-4-ylmethoxy)benzamide;-   N-cyclopropyl-4-methyl-3-{[3-methyl-4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide;-   N-cyclopropyl-4-methyl-3-{[3-methyl-4-(1,3-thiazol-4-ylmethoxy)benzoyl]amino}benzamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-ylmethoxy)benzamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluorobenzamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(1,2,5-thiadiazol-3-ylmethoxy)benzamide;-   N-cyclopropyl-4-methyl-3-{[3-(1,3-thiazol-4-ylmethoxy)benzoyl]amino}benzamide;-   N-cyclopropyl-4-methyl-3-({3-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzoyl}amino)benzamide;-   N-cyclopropyl-4-methyl-3-{[3-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(1,3-thiazol-4-ylmethoxy)benzamide;-   N-cyclopropyl-4-methyl-3-({3-methyl-4-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzoyl}amino)benzamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-methylbenzamide;-   N-cyclopropyl-4-methyl-3-{[3-methyl-4-(1,2,5-thiadiazol-3-ylmethoxy)benzoyl]amino}benzamide;-   methyl    5-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]-2-methylphenoxy}methyl)-2-furoate;-   3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-(pyridin-2-ylmethoxy)benzamide;-   3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-(1,3-thiazol-4-ylmethoxy)benzamide;-   N-cyclopropyl-3-({3-[(3,5-dimethylisoxazol-4-yl)methoxy]benzoyl}amino)-4-methylbenzamide;-   N-cyclopropyl-4-methyl-3-{[3-(1,2,5-thiadiazol-3-ylmethoxy)benzoyl]amino}benzamide;-   3-({3-[(2-chloro-1,3-thiazol-5-yl)methoxy]benzoyl}amino)-N-cyclopropyl-4-methylbenzamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methyl-phenyl}-3-fluoro-4-(imidazo[1,2-a]pyridin-2-ylmethoxy)benzamide;-   N-cyclopropyl-3-({4-[(4-methoxypyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide;-   N-cyclopropyl-4-methyl-3-{[4-(1-pyridin-2-ylethoxy)benzoyl]amino}benzamide;-   N-cyclopropyl-3-({3-[(4-methoxypyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide;-   N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide;-   N-cyclopropyl-3-[(4-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide;-   N-cyclopropyl-3-{[4-({5-[(isopropylamino)methyl]pyridin-2-yl}methoxy)benzoyl]amino}-4-methylbenzamide;-   N-cyclopropyl-3-{[4-({5-[(dimethylamino)methyl]pyridin-2-yl}methoxy)benzoyl]amino}-4-methylbenzamide;-   methyl    6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}methyl)nicotinate;-   N-cyclopropyl-3-{[4-({5-[2-(dimethylamino)ethoxy]pyridin-2-yl}methoxy)benzoyl]amino}-4-methylbenzamide;-   N-cyclopropyl-3-[(4-{[5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide;-   N-cyclopropyl-3-({4-[(5-hydroxypyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide-   methyl    6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}methyl)pyridine-2-carboxylate;-   N-cyclopropyl-3-[(4-{[6-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide;-   N-cyclopropyl-3-[(4-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methoxy)benzoyl}amino]-4-methylbenzamide;-   N-cyclopropyl-3-({4-[(6-{[2-(diethylamino)ethoxy]methyl}pyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide;-   N-cyclopropyl-3-({4-[(6-{[2-(dimethylamino)ethoxy]methyl}pyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide;-   N-cyclopropyl-4-methyl-3-({4-[(1-oxidopyridin-2-yl)methoxy]benzoyl}amino)benzamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyrimidine-5-carboxamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(1,3-thiazol-2-ylmethoxy)pyrimidine-5-carboxamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(pyrimidin-2-ylmethoxy)pyrimidine-5-carboxamide;-   {5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1-methyl-1H-imidazol-2-yl)methoxy]pyrimidine-5-carboxamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1,5-dimethyl-1H-pyrazol-3-yl)methoxy]pyrimidine-5-carboxamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]pyrimidine-5-carboxamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(3-methylpyridin-2-yl)methoxy]pyrimidine-5-carboxamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1-methyl-1H-benzimidazol-2-yl)methoxy]pyrimidine-5-carboxamide;-   {5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(isoquinolin-1-ylmethoxy)pyrimidine-5-carboxamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(quinolin-2-ylmethoxy)pyrimidine-5-carboxamide;-   2-(1,3-benzothiazol-2-ylmethoxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyrimidine-5-carboxamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-pyridin-2-ylethoxy)pyrimidine-5-carboxamide;-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(1,3-thiazol-4-ylmethoxy)pyrimidine-5-carboxamide;-   {5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(pyridin-2-ylmethoxy)pyrimidine-5-carboxamide;-   N-cyclopropyl-3-({4-[(5-cyclopropyl-1,3,4-thiadiazol-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide;-   {5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-6-(pyridin-2-ylmethoxy)nicotinamide;-   {5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)pyrazine-2-carboxamide;-   3-({4-[(6-bromopyridin-2-yl)methoxy]benzoyl}amino)-N-cyclopropyl-4-methylbenzamide-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,5-difluoro-4-(pyridin-2-ylmethoxy)benzamide;-   N-cyclopropyl-4-methyl-3-({4-[(6-methylpyridin-2-yl)methoxy]benzoyl}amino)benzamide;-   N-cyclopropyl-4-methyl-3-({4-[(3-methylpyridin-2-yl)methoxy]benzoyl}amino)benzamide;-   N-cyclopropyl-4-methyl-3-{[4-(pyrimidin-2-ylmethoxy)benzoyl]amino}benzamide;-   N-cyclopropyl-4-methyl-3-{[4-(pyridazin-3-ylmethoxy)benzoyl]amino}benzamide;-   N-cyclopropyl-3-{[4-({6-[(2-methoxyethyl)amino]pyridin-2-yl}methoxy)benzoyl]amino}-4-methylbenzamide;-   N-cyclopropyl-3-({4-[(6-{[2-(dimethylamino)ethyl]amino}pyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide;-   5-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyridine-2-carboxamide-   N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)pyridine-2-carboxamide;    and-   N-cyclopropyl-4-methyl-3-[(4-{[4-(methylsulfonyl)benzyl]oxy}benzoyl)amino]benzamide;-   or a pharmaceutically-acceptable salt thereof.

Compounds of the Formula I, or a pharmaceutically-acceptable saltsthereof, may be prepared by any process known to be applicable to thepreparation of chemically-related compounds. Suitable processes areillustrated by, for example, those in WO 00/07980. Such processes, whenused to prepare a novel compound of the Formula I are provided as afurther feature of the invention and are illustrated by the followingrepresentative process variants in which, unless otherwise stated,Q_(a), Q_(b), R₁ and R₂ have any of the meanings defined hereinbefore.Necessary starting materials may be obtained by standard procedures oforganic chemistry. The preparation of such starting materials isdescribed in conjunction with the following representative processvariants and within the accompanying Examples. Alternatively necessarystarting materials are obtainable by analogous procedures to thoseillustrated which are within the ordinary skill of an organic chemist.

(a) A compound of the Formula I, or a pharmaceutically-acceptable saltthereof, may be prepared by reacting a benzoic acid of the Formula II,or a activated derivative thereof,

with an amine of the Formula III

under standard amide bond forming conditions, wherein Q_(a), Q_(b), R₁and R₂ are as defined hereinbefore and wherein any functional group isoptionally protected, and:

(i) removing any protecting groups; and

(ii) optionally forming a pharmaceutically-acceptable salt.

A suitable activated derivative of an acid of the Formula II is, forexample, an acyl halide, for example an acyl chloride formed by thereaction of the acid and an inorganic acid chloride, for example thionylchloride; a mixed anhydride, for example an anhydride formed by thereaction of the acid and a chloroformate such as isobutyl chloroformate;an active ester, for example an ester formed by the reaction of the acidand a phenol such as pentafluorophenol, an ester such aspentafluorophenyl trifluoroacetate or an alcohol such asN-hydroxybenzotriazole; an acyl azide, for example an azide formed bythe reaction of the acid and an azide such as diphenylphosphoryl azide;an acyl cyanide, for example a cyanide formed by the reaction of an acidand a cyanide such as diethylphosphoryl cyanide; or the product of thereaction of the acid and a carbodiimide such asdicyclohexylcarbodiimide.

The reaction is preferably carried out in the presence of a suitablebase such as, for example, an alkali or alkaline earth metal carbonate,alkoxide, hydroxide or hydride, for example sodium carbonate, potassiumcarbonate, sodium ethoxide, potassium butoxide, sodium hydroxide,potassium hydroxide, sodium hydride or potassium hydride, or anorganometallic base such as an alkyl-lithium, for examplen-butyl-lithium, or a dialkylamino-lithium, for example lithiumdi-isopropylamide, or, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene. Thereaction is also preferably carried out in a suitable inert solvent ordiluent, for example tetrahydrofuran, methylene chloride,1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at atemperature in the range, for example, −78 to 150° C., conveniently ator near ambient temperature.

Typically a carbodiimide coupling reagent is used in the presence of anorganic solvent (preferably an anhydrous polar aprotic organic solvent)at a non-extreme temperature, for example in the region −10 to 40° C.,typically at ambient temperature of about 20° C.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question and may beintroduced by conventional methods. Protecting groups may be removed byany convenient method as described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with minimum disturbance of groups elsewhere in themolecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower”, as in, for example, lower alkyl signifiesthat the group to which it is applied preferably has 1-4 carbon atoms.It will be understood that these examples are not exhaustive. Wherespecific examples of methods for the removal of protecting groups aregiven below these are similarly not exhaustive. The use of protectinggroups and methods of deprotection not specifically mentioned is ofcourse within the scope of the invention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(1-12C)alkyl groups (for example isopropyl, tert-butyl); lower alkoxylower alkyl groups (for example methoxymethyl, ethoxymethyl,isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (forexample acetoxymethyl, propionyloxymethyl, butyryloxymethyl,pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (forexample 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl loweralkyl groups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups(for example trimethylsilyl and tert-butyldimethylsilyl); tri(lowerallyl)silyl lower alkyl groups (for example trimethylsilylethyl); and(2-6C)alkenyl groups (for example allyl and vinylethyl). Methodsparticularly appropriate for the removal of carboxyl protecting groupsinclude for example acid-, base-, metal- or enzymically-catalysedhydrolysis.

Examples of hydroxy protecting groups include lower alkyl groups (forexample tert-butyl), lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for examplebenzoyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkylsilyl (for example trimethylsilyl, tert-butyldimethylsilyl) andaryl lower alkyl (for example benzyl) groups.

Examples of amino protecting groups include formyl, aralkyl groups (forexample benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl andfurylmethyl groups; lower alkoxycarbonyl (for exampletert-butoxycarbonyl); lower alkenyloxycarbonyl (for exampleallyloxycarbonyl); aryl lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl andtert-butyldimethylsilyl); allylidene (for example methylidene);benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis for groups such as p-nitrobenzyloxycarbonyl, hydrogenationfor groups such as benzyl and photolytically for groups such aso-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry, 4th Edition, byJerry March, published by John Wiley & Sons 1992, for general guidanceon reaction conditions and reagents. The reader is referred toProtective Groups in Organic Synthesis, 3rd Edition, by Green and Wuts,published by John Wiley & Sons for general guidance on protectinggroups.

The benzoic acid of Formula II may be prepared by the cleavage of thecorresponding ester thereof which, in turn, may be prepared by reactionof an acid of Formula IV wherein Q_(a), Q_(b), R₁ and R₂ are as definedhereinbefore, or an activated derivative thereof as definedhereinbefore,

with an aniline of Formula V

wherein R is, for example, lower alkyl or benzyl, under suitable amidebond forming conditions as defined hereinbefore.

Typical conditions include activating the carboxy group of the compoundof Formula IV, for example by treatment with a halo reagent (for exampleoxalyl chloride) to form an acyl halide in an organic solvent at ambienttemperature and then reacting the activated compound with the aniline ofFormula V. Any functional groups are protected and deprotected asnecessary.

(b) A compound of the Formula I, or a pharmaceutically-acceptable saltthereof, may be prepared by reacting an acid of the Formula N, or anactivated derivative thereof as defined hereinbefore,

with an aniline of the Formula VI

under standard amide bond forming conditions as defined hereinbefore,wherein Q_(a), Q_(b), R₁ and R₂ are as defined hereinbefore and whereinany functional group is optionally protected, and:

(i) removing any protecting groups;

(ii) optionally forming a pharmaceutically-acceptable salt.

The aniline of Formula VI may be prepared by reduction of thecorresponding nitro compound using convention procedures such as thoseillustrated in the Examples. Typical reaction conditions include the useof ammonium formate or hydrogen gas in the presence of a catalyst (forexample palladium-on-carbon) in the presence of an organic solvent(preferably a polar protic solvent), preferably with heating, forexample to about 60° C. Any functional groups are protected anddeprotected as necessary.

(c) A compound of the Formula I wherein a substituent on Q_(a) or Q_(b)is (1-6C)alkoxy or substituted (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino or substituted (1-6C)alkylamino, may be preparedby the alkylation, conveniently in the presence of a suitable base asdefined hereinbefore, of an amide derivative of the Formula I wherein asubstituent on Q_(a) or Q_(b) is hydroxy or amino as appropriate.

The reaction is preferably carried out in the presence of a suitableinert solvent or diluent, for example a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride, an ether such astetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or adipolar aprotic solvent such as N,N-dimethylformamide,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide. Thereaction is conveniently carried out at a temperature in the range, forexample, 10 to 150° C., preferably in the range 20 to 80° C.

A suitable alkylating agent is, for example, any agent known in the artfor the alkylation of hydroxy to alkoxy or substituted alkoxy, or forthe alkylation of mercapto to alkylthio, or for the alkylation of aminoto alkylamino or substituted alkylamino, or for the alkylation ofhydroxy to heterocyclyloxy, for example an alkyl or substituted alkylhalide, for example a (1-6C)alkyl chloride, bromide or iodide or asubstituted (1-6C)alkyl chloride, bromide or iodide or a heterocyclylchloride, bromide or iodide, in the presence of a suitable base asdefined hereinbefore.

(d) A compound of the Formula I wherein a substituent on Q_(a) or Q_(b)is (1-6C)alkanoylamino or substituted (2-6C)alkanoylamino may beprepared by the acylation of a compound of the Formula I wherein asubstituent on Q_(a) or Q_(b) is amino.

A suitable acylating agent is, for example, any agent known in the artfor the acylation of amino to acylamino, for example an acyl halide, forexample a (1-6C)alkanoyl chloride or bromide, conveniently in thepresence of a suitable base, as defined hereinbefore, an alkanoic acidanhydride or mixed anhydride, for example a (1-6C)alkanoic acidanhydride such as acetic anhydride or the mixed anhydride formed by thereaction of an alkanoic acid and a (1-6C)alkoxycarbonyl halide, forexample a (1-6C)alkoxycarbonyl chloride, in the presence of a suitablebase as defined hereinbefore. In general the acylation is carried out ina suitable inert solvent or diluent as defined hereinbefore and at atemperature, in the range, for example, −30 to 120° C., conveniently ator near ambient temperature.

(e) A compound of the Formula I wherein a substituent on Q_(b) is(1-6C)alkanesulphonylamino may be prepared by the reaction of a compoundof the Formula I wherein a substituent on Q_(b) is amino with a(1-6C)alkanesulphonic acid, or an activated derivative thereof.

A suitable activated derivative of a (1-6C)alkanesulphonic acid is, forexample, an alkanesulphonyl halide, for example an alkanesulphonylchloride formed by the reaction of the sulphonic acid and an inorganicacid chloride, for example thionyl chloride. The reaction is preferablycarried out in the presence of a suitable base as defined hereinbefore,particularly pyridine, and in a suitable inert solvent or diluent asdefined hereinbefore, particularly methylene chloride.

(f) A compound of the Formula I wherein a substituent on Q_(a) or Q_(b)is amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, may be prepared by the reaction of acompound of the Formula I wherein a substituent on Q_(b) is a group ofthe formula -(1-6C)alkylene-Z wherein Z is a displaceable group with anappropriate amine.

A suitable displaceable group Z is, for example, a halogen group such asfluoro, chloro or bromo, a (1-6C)alkanesulphonyloxy group such asmethanesulphonyloxy or an arylsulphonyloxy group such as4-toluenesulphonyloxy.

The reaction is conveniently carried out in the presence of a suitablebase as defined hereinbefore and in the presence of a suitable inertdiluent or carrier as defined hereinbefore. The reaction is convenientlycarried out at a temperature in the range 10 to 150° C., preferably ator near 50° C.

(g) A compound of the Formula I wherein a substituent on Q_(a) or Q_(b)is an amino group may be prepared by the reduction of a compound of theFormula I wherein a substituent on Q_(a) or Q_(b) is a nitro group.

Typical reaction conditions include the use of ammonium formate orhydrogen gas in the presence of a catalyst, for example a metalliccatalyst such as palladium-on-carbon. Alternatively a dissolving metalreduction may be carried out; for example using iron in the presence ofan acid, for example an inorganic or organic acid such as hydrochloric,hydrobromic, sulphuric or acetic acid. The reaction is convenientlycarried out in the presence of an organic solvent (preferably a polarprotic solvent) and preferably with heating, for example to about 60° C.Any functional groups are protected and deprotected as necessary.

The following biological assays and Examples serve to illustrate thepresent invention.

Biological Assays

The following assays can be used to measure the p38 kinase-inhibitory,the TNF-inhibitory and anti-arthritic effects of compounds of theFormula I:

In Vitro Enzyme Assay

The ability test compounds to inhibit the enzyme p38 kinase wasassessed. Activity of the test compound against each of the p38α andp3811 isoforms of the enzyme was determined.

Human recombinant MKK6 (GenBank Accession Number G1209672) was isolatedfrom Image clone 45578 (Genomics, 1996, 33, 151) and utilised to produceprotein in the form of a GST fusion protein in a pGEX vector usinganalogous procedures to those disclosed by J. Han et al., Journal ofBiological Chemistry, 1996, 271, 2886-2891. p38α (GenBank AccessionNumber G529039) and p38β (GenBank Accession Number G1469305) wereisolated by PCR amplification of human lymphoblastoid cDNA (GenBankAccession Number GM1416) and human foetal brain cDNA [synthesised frommRNA (Clontech, catalogue no. 6525-1) using a Gibco superscript cDNAsynthesis kit] respectively using oligonucleotides designed for the 5′and 3′ ends of the human p38α and p38β genes using analogous proceduresto those described by J. Han et al., Biochimica et Biophysica Acta,1995, 1265, 224-227 and Y. Jiang et al., Journal of BiologicalChemistry, 1996, 271, 17920-17926.

Both p38 protein isoforms were expressed in E. coli in PET vectors.Human recombinant p38α and p38β isoforms were produced as 5′ c-myc, 6Histagged proteins. Both MKK6 and the p38 proteins were purified usingstandard protocols: the GST MKK6 was purified using a glutathionesepharose column and the p38 proteins were purified using nickel chelatecolumns.

The p38 enzymes were activated prior to use by incubation with MKK6 for3 hours at 30° C. The unactivated E. coli-expressed MKK6 retainedsufficient activity to fully activate both isoforms of p38. For p38α,the activation incubate comprised p38α (50 μl of 10 mg/ml), MKK6 (5 μlof 12 mg/ml), ‘Kinase buffer’ [550 μl; pH 7.4 buffer comprising Tris HCl(50 mM), EGTA (0.1 mM), sodium orthovanadate (0.1 mM) and(1-mercaptoethanol (0.1%)], Mg [75 μl of 100 mM Mg(OCOCH₃)₂] and ATP (75μl of 1 mM). The activation incubate for p38β was similar to the aboveexcept containing p383 enzyme (82 μl at 3.05 mg/ml) and 518 μl “Kinasebuffer”. p38α and p38β activation incubates were either used fresh oraliquoted and stored at −80° C.

The test compound was solubilised in DMSO (10 mM) and 1:3 serialdilutions in DMSO carried out in polypropylene plates (Costar 3365).Compound dilutions were then diluted 1:10 in “Kinase buffer” and 10 μltransferred to a microtiter assay plate (Costar 3596). Control wellscontained 10 μl (1:10 dilution in kinase buffer) DMSO. ‘Kinase AssayMix’ [301.1.1; comprising Myelin Basic Protein (Sigma M-1891; 0.5 ml ofa 6.66 mg/ml solution in “Kinase buffer”), activated p38α enzyme (3.8μl) and ‘Kinase Buffer’ (2.55 ml)] was then added. Control wells on eachplate either contained the above “Kinase Assay Mix” (n=6 replicates) orcontained “Kinase Assay Mix” in which the activated p38 enzyme wasreplaced by Kinase buffer (n=6 replicates). ‘Labelled ATP’ was thenadded to all wells DOW; comprising 50 μM ATP, 5 μCi ³³P ATP (AmershamInternational cat. no. AH9968) and 50 mM Mg(OCOCH₃)₂]. For p38β, 23 μlactivated p38β enzyme and “Kinase buffer” (2.53 ml) were included in the“Kinase Assay Mix”. The final concentration of test compound was 2.4μM-0.001 μM (n=2 replicates). Microtiter plates were incubated atambient temperature (with gentle agitation) for 60 minutes and thereaction stopped by addition of 20% trichloroacetic acid (TCA) (50 μl).The precipitate protein was captured onto filter plates (PerkinElmer6005174) using a Packard Filtermate harvester (2% TCA wash) which wasthen dried overnight and 25 μl MICROSCINT O (Packard O6013611) added toeach well. Plates were counted on a Top Count scintillation counter.Dose response curves were generated using an in house automated dataanalysis package and an Origin curve fitting package.

In Vitro Cell-Based Assays

(i) PBMC

The ability of a test compound to inhibit TNFα production was assessedby using human peripheral blood mononuclear cells which synthesise andsecrete TNFα when stimulated with lipopolysaccharide (LPS).

Peripheral blood mononuclear cells (PBMC) were isolated from heparinised(10 units/ml heparin) human blood by density centrifugation(Lymphoprep™; Nycomed). Mononuclear cells were resuspended in “CultureMedium” [RPMI 1640 medium (Sigma R0883) containing 50 units/mlpenicillin, 50 μg/ml streptomycin and 2 mM glutamine] supplemented with1% heat-inactivated human AB serum (Sigma H-1513)]. Compounds weresolubilised in DMSO at a concentration of 20 mM, diluted 1:100 in“culture medium” and serial dilutions carried out in “Culture Medium”containing 1% DMSO. PBMCs (2.2×10⁵ cells in 160 μl culture medium) wereincubated with 20 μl of varying concentrations of test compound(duplicate cultures) or 20 μl culture medium containing 1% DMSO (controlwells) for 30 minutes at 37° C. in a humidified (5% CO₂/95% air)incubator (Corning 3595; 96 well flat-bottom tissue culture plates). 20μl lipopolysaccharide [LPS E. Coli 0111:B4 (Sigma L-4130), finalconcentration 0.1 μg/ml] solubilised in “Culture Medium” was added toappropriate wells. 20 μl Culture Medium was added to “medium alone”control wells. Six “LPS alone” and six “medium alone” controls wereincluded on each 96 well plate.

The test compound was tested for TNFα inhibitory activity over a finalconcentration dose range of 20 μM-0.0001 μM. Each test included a knownTNFα inhibitor i.e. the p38 MAPK inhibitor, SB203580 (Lee, J. C., et al(1994) Nature 372 p739-746). Plates were incubated for 24 hours at 37°C. (humidified incubator) after which 100 μl of the supernatant wasremoved from each well and stored at −80° C. (96 well round-bottomplates; Corning 3799). TNFα levels were determined in each sample usinga human TNFα ELISA (using R&D Systems paired antibodies, MAB610 andBAF210.

${\%\mspace{14mu}{inhibition}} = {\frac{\begin{matrix}{\left( {{{LPS}\mspace{14mu}{alone}} - {{medium}\mspace{14mu}{alone}}} \right) -} \\\left( {{{test}\mspace{14mu}{concentration}} - {{medium}\mspace{14mu}{alone}}} \right)\end{matrix}}{\left( {{{LPS}\mspace{14mu}{alone}} - {{medium}\mspace{14mu}{alone}}} \right)} \times 100}$(ii) Human Whole Blood

The ability of a test compound to inhibit TNFα production was alsoassessed in a human whole blood assay. Human whole blood secretes TNFαwhen stimulated with LPS.

Heparinised (10 units/ml) human blood was obtained from volunteers. 160μl whole blood was added to 96 well round-bottom plates (Corning 3799).Compounds were solubilised in DMSO at a concentration of 10 mM, diluted1:100 in “culture medium” [RPMI 1640 medium (Sigma) containing 50units/ml penicillin, 50 μg/ml streptomycin and 2 mM glutamine] andsubsequently serial dilutions were made in culture medium containing 1%DMSO. 20 μl of each test concentration was added to appropriate wells(triplicate cultures)(final concentration dose range of 10 μM-0.0001μM). 20 μl of RPMI culture medium containing 1% DMSO was added tocontrol wells.

Plates were incubated for 30 minutes at 37° C. (humidified incubator),prior to addition of 20 μl LPS (final concentration 10 μg/ml). Culturemedium was added to control wells. Six “LPS alone” and six “mediumalone” controls were included on each plate. A known TNFαsynthesis/secretion inhibitor was included in each test. Plates wereincubated for 6 hours at 37° C. (humidified incubator). Plates werecentrifuged (2000 rpm for 10 minutes) and 80 μl plasma removed andstored at −80° C. (Corning 3799 plates). TNFα levels were measured byELISA using paired antibodies from R&D Systems (catalogue nos. MAB610and BAF210).

In Vivo Assessment

The ability of a test compound to inhibit TNFα synthesis in vivo wasassessed in a rat lipopolysaccharide (LPS)-challenge model. Briefly,compound was dosed orally (100-0.3 mg/kg in 20% DMSO (Sigma D-2650)/60%PEG 400 (Fisher Scientific P/3676/08)/20% sterile de-ionised water; 5animals per group) to female Wistar Alderley Park (AP) rats (80-100 g)at appropriate timepoints prior to challenge with LPS. Control animals(10 per group) were dosed vehicle alone. LPS (LPS E. Coli 0111:B4; SigmaL-4130) was administered intravenously (30 μg in 0.2 ml sterilephysiological saline (Phoenix Pharma Ltd). A control group werechallenged with 0.2 ml sterile physiological saline. Blood was obtained60 minutes later from anaesthetised animals and serum isolated after 2hours incubation at ambient temperature (Sarstedt serum separator 1 mlmicrotubes, ref 41.1500.005) and centrifugation. Serum samples werestored at −80° C. prior to determination of TNFα content by ELISA (R&DSystems rat TNFα Quantikine kit, catalogue no. SRTA00). % inhibitionTNFα calculated as100−[(compound treated−saline control)/LPS control−saline control)×100]Test as Anti-Arthritic Agent

Compound was tested for activity in a rat streptococcalcell-wall-induced arthritis model (SCW) [for further information seeCarlson, R. P. and Jacobsen, P. B. (1999) Comparison of adjuvant andstreptococcal cell-wall-induced arthritis in the rat. In In Vivo Modelsof Inflammation, eds Morgan, D. W. and Marshall, L. A., BirkhauserVerlag, Basel, Switzerland].

Briefly, female Lewis rats (160-180 g) were sensitised byintra-articular injection of 5 μg streptococcal cell wall (Lee Labs,PG-PS 100P) in 20 μl sterile physiological saline into the left ankle.Responsiveness was assessed 3 days later and animals randomised.Arthritis was induced 21 days after sensitisation (designated day 0) byintravenous injection of 100 μg scw (in 500 μl sterile physiologicalsaline). Compound was dosed orally (50-1 mg/kg once daily) (4 ml/kg)either before (day-1) or after disease onset (day+1) (10 animals pertest group; vehicle 0.5% (w/v) HPMC and 0.1% (w/v) polysorbate 80).Control animals (n=10) received vehicle alone. “Non-induced” controlanimals which were dosed with vehicle were also included (5 animals pergroup). Animals were weighed on a daily basis from day-1 and anklediameters measured with Vernier callipers on a daily basis from day-1.At termination on day 6, left hind limbs were removed and fixed in 10%formalin for histological assessment.

Although the pharmacological properties of the compounds of the FormulaI vary with structural change as expected, in general a compound of theFormula a gives over 50% inhibition of p38α and/or p38β atconcentrations less than 1 μM. No physiologically unacceptable toxicitywas observed at the effective dose for compounds tested of the presentinvention.

The following table shows IC₅₀ figures for a representative selection ofcompounds according to the invention, as well as for the ComparatorCompound X disclosed in WO 00/07980 when tested in the above assays:

Human Whole Example p38α (μM) Blood (μM) Comparator 4.4 >10 Compound X 5[ac] 0.007 0.07  5[e] 0.01 0.52  5[y] 0.006 0.14  5[z] 0.007 0.30  80.059 1.8 23[a] 0.17 1.7

According to a further aspect of the invention there is provided apharmaceutical composition which comprises compound of the Formula I, ora pharmaceutically-acceptable salt thereof, in association with apharmaceutically-acceptable diluent or carrier.

According to a further aspect of the invention there is provided apharmaceutical composition for use in the treatment of diseases mediatedby cytokines which comprises compound of the Formula I, or apharmaceutically-acceptable salt thereof, in association with apharmaceutically-acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent compounded with an appropriate andconvenient amount of excipients which may vary from about 5 to about 98percent by weight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula I of the invention will naturally vary accordingto the nature and severity of the conditions, the age and sex of theanimal or patient and the route of administration, according to wellknown principles of medicine.

In using a compound of the Formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used. Oral administration is howeverpreferred, particularly in tablet form. Typically, unit dosage formswill contain about 1 mg to 500 mg of a compound of this invention.

According to a further aspect of the invention there is provided acompound of the Formula I, or a pharmaceutically-acceptable saltthereof, for use in a method of treatment of the human or animal body bytherapy.

According to a further aspect of the invention there is provided the useof a compound of the Formula I, or a pharmaceutically-acceptable saltthereof, in the manufacture of a medicament.

According to a further aspect of the invention there is provided the useof a compound of the Formula I, or a pharmaceutically-acceptable saltthereof, in the manufacture of a medicament for use in the treatment ofmedical conditions mediated by cytokines.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by cytokines which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt thereof.

In a further aspect the present invention provides a method of treatinga disease or medical condition mediated by cytokines which comprisesadministering to a warm-blooded animal in need thereof a cytokineinhibiting amount of a compound of the Formula I, or apharmaceutically-acceptable salt thereof.

In a further aspect the present invention provides a method of treatinga disease or medical condition mediated by the production or effect ofcytokines which comprises administering to a warm-blooded animal in needthereof a cytokine inhibiting amount of a compound of the Formula I, ora pharmaceutically-acceptable salt thereof.

In a further aspect on the invention there is provided a method forinhibiting the production or effect of a cytokine in a warm-bloodedanimal in need thereof a p38 kinase inhibiting amount of a compound ofthe Formula I, or a pharmaceutically-acceptable salt thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt thereof, in themanufacture of a medicament for use in the treatment of diseases ormedical conditions mediated by TNF, IL-1, IL-6 or IL-8.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8 whichcomprises administering to a warm-blooded animal an effective amount ofa compound of the Formula I, or a pharmaceutically-acceptable saltthereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt thereof in themanufacture of a medicament for use in the treatment of diseases ormedical conditions mediated by TNF.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt thereof, in themanufacture of a medicament for use in inhibiting TNF, IL-1, IL-6 orIL-8.

In a further aspect the present invention provides a method ofinhibiting TNF, IL-1, IL-6 or IL-8 which comprises administering to awarm-blooded animal an effective amount of a compound of the Formula I,or a pharmaceutically-acceptable salt thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt thereof, in themanufacture of a medicament for use in inhibiting TNF.

In a further aspect the present invention provides a method ofinhibiting TNF which comprises administering to a warm-blooded animal aneffective amount of a compound of the Formula I, or apharmaceutically-acceptable salt thereof.

In a further aspect the present invention provides a compound of theFormula I, or a pharmaceutically-acceptable salt thereof, in themanufacture of a medicament for use in the treatment of diseases ormedical conditions mediated by p38 kinase.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by p38 kinase which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt thereof, in themanufacture of a medicament for use in the production of a p38 kinaseinhibitory effect.

In a further aspect the present invention provides a method of providinga p38 kinase inhibitory effect which comprises administering to awarm-blooded animal an effective amount of a compound of the Formula I,or a pharmaceutically-acceptable salt thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable thereof, in themanufacture of a medicament for use in the treatment of rheumatoidarthritis, asthma, chronic obstructive pulmonary disease, inflammatorybowel disease, multiple sclerosis, AIDS, septic shock, congestive heartfailure, ischaemic heart disease or psoriasis.

In a further aspect the present invention provides a method of treatingrheumatoid arthritis, asthma, chronic obstructive pulmonary disease,inflammatory bowel disease, multiple sclerosis, AIDS, septic shock,congestive heart failure, ischaemic heart disease or psoriasis whichcomprises administering to a warm-blooded animal an effective amount ofa compound of the Formula I, or a pharmaceutically-acceptable saltthereof.

A compound of the Formula I may be used in combination with other drugsand therapies used in the treatment of disease states which wouldbenefit from the inhibition of cytokines, in particular TNF and IL-1.For example, a compound of the Formula I could be used in combinationwith drugs and therapies used in the treatment of rheumatoid arthritis,asthma, chronic obstructive pulmonary disease, inflammatory boweldisease, multiple sclerosis, AIDS, septic shock, congestive heartfailure, ischaemic heart disease, psoriasis and the other disease statesmentioned earlier in this specification.

For example, by virtue of its ability to inhibit cytokines, a compoundof the Formula I is of value in the treatment of certain inflammatoryand non-inflammatory diseases which are currently treated with acyclooxygenase-inhibitory non-steroidal anti-inflammatory drug (NSAID)such as indomethacin, ketorolac, acetylsalicyclic acid, ibuprofen,sulindac, tolmetin and piroxicam. Co-administration of a compound of theFormula I of the present invention with a NSAID can result in areduction of the quantity of the latter agent needed to produce atherapeutic effect. Thereby the likelihood of adverse side-effects fromthe NSAID such as gastrointestinal effects are reduced. Thus accordingto a further feature of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the Formula I, or apharmaceutically-acceptable salt thereof, in conjunction or admixturewith a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent,and a pharmaceutically-acceptable diluent or carrier.

A compound of the Formula I may also be used with anti-inflammatoryagents such as an inhibitor of the enzyme 5-lipoxygenase.

A compound of the Formula I may also be used in the treatment ofconditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpencillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

A compound of the Formula I may also be administered in degradativediseases, for example osteoarthritis, with chondroprotective,anti-degradative and/or reparative agents such as Diacerhein, hyaluronicacid formulations such as Hyalan, Rumalon, Arteparon and glucosaminesalts such as Antril.

A compound of the Formula I may be used in the treatment of asthma incombination with antiasthmatic agents such as steroids, bronchodilatorsand leukotriene antagonists.

In particular, for the treatment of the inflammatory diseases rheumatoidarthritis, psoriasis, inflammatory bowel disease, chronic obstructivepulmonary disease, asthma and allergic rhinitis a compound of thepresent invention may be combined with agents such as TNF-α inhibitorssuch as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 andD.sub2.E.sub7.) and TNF receptor immunoglobulin molecules (such asEnbrel.reg.), non-selective COX-1/COX-2 inhibitors (such as piroxicam,diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin), COX-2 inhibitors (such as meloxicam,celecoxib, rofecoxib, valdecoxib and etoricoxib) low dose methotrexate,lefimomide; ciclesonide; hydroxychloroquine, d-penicillamine, auranofinor parenteral or oral gold.

The present invention still further relates to the combination of acompound of the Formula I together with a leukotriene biosynthesisinhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activatingprotein (FLAP) antagonist such as zileuton; ABT-761; fenleuton;tepoxalin; Abbott-79175; Abbott-85761;N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenolhydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compoundSB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such asL-739,010; 2-cyanoquinoline compounds such as L-746,530; indole andquinoline compounds such as MK-591, MK-886, and BAY x 1005.

The present invention still further relates to the combination of acompound of the Formula I together with a receptor antagonist forleukotrienes LTB.sub4., LTC.sub4., LTD.sub4., and LTE.sub4. selectedfrom the group consisting of the phenothiazin-3-ones such as L-651,392;amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast;benzenecarboximidamides such as BIIL 284/260; and compounds such aszafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),RG-12525, Ro-245913, iralulcast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of acompound of the Formula I together with a PDE4 inhibitor includinginhibitors of the isoform PDE4D.

The present invention still further relates to the combination of acompound of the Formula I together with a antihistaminic H.sub1.receptor antagonists such as cetirizine, loratadine, desloratadine,fexofenadine, astemizole, azelastine, and chlorpheniramine.

The present invention still further relates to the combination of acompound of the Formula I together with a gastroprotective H.sub2.receptor antagonist.

The present invention still further relates to the combination of acompound of the Formula I together with an α.sub1.- andα.sub2.-adrenoceptor agonist vasoconstrictor sympathomimetic agent, suchas propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine,naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, and ethylnorepinephrinehydrochloride.

The present invention still further relates to the combination of acompound of the Formula I together with anticholinergic agents such asipratropium bromide; tiotropium bromide; oxitropium bromide;pirenzepine; and telenzepine.

The present invention still further relates to the combination of acompound of the Formula I together with a β.sub1.- toβ.sub4.-adrenoceptor agonists such as metaproterenol, isoproterenol,isoprenaline, albuterol, salbutamol, formoterol, salmeterol,terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; ormethylxanthanines including theophylline and aminophylline; sodiumcromoglycate; or muscarinic receptor (M1, M2, and M3) antagonist.

The present invention still further relates to the combination of acompound of the Formula I together with an insulin-like growth factortype I (IGF-1) mimetic.

The present invention still further relates to the combination of acompound of the Formula I together with an inhaled glucocorticoid withreduced systemic side effects, such as prednisone, prednisolone,flunisolide, triamcinolone acetonide, beclomethasone dipropionate,budesonide, fluticasone propionate, and mometasone furoate.

The present invention still further relates to the combination of acompound of the Formula I together with an inhibitor of matrixmetalloproteases (MMPs), i.e., the stromelysins, the collagenases, andthe gelatinases, as well as aggrecanase; especially collagenase-1(MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1(MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-12.

The present invention still further relates to the combination of acompound of the Formula I together with other modulators of chemokinereceptor function such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1,CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX₃CR1 for the C—X₃—Cfamily.

The present invention still further relates to the combination of acompound of the Formula I together with antiviral agents such asViracept, AZT, aciclovir and famciclovir, and antisepsis compounds suchas Valant.

The present invention still further relates to the combination of acompound of the Formula I together with cardiovascular agents such ascalcium channel blockers, lipid lowering agents such as statins,fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptorantagonists and platelet aggregation inhibitors.

The present invention still further relates to the combination of acompound of the Formula I together with CNS agents such asantidepressants (such as sertraline), anti-Parkinsonian drugs (such asdeprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine andrasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopaminereuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamineagonists and inhibitors of neuronal nitric oxide synthase), andanti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors,propentofylline or metrifonate.

The present invention still further relates to the combination of acompound of the Formula I together with (i) tryptase inhibitors; (ii)platelet activating factor (PAF) antagonists; (iii) interleukinconverting enzyme (ICE) inhibitors; (iv) IMPDH inhibitors; (v) adhesionmolecule inhibitors including VLA-4 antagonists; (vi) cathepsins; (vii)MAP kinase inhibitors; (viii) glucose-6 phosphate dehydrogenaseinhibitors; (ix) kinin-B.sub 1.- and B.sub2.-receptor antagonists; (x)anti-gout agents, e.g., colchicine; (xi) xanthine oxidase inhibitors,e.g., allopurinol; (xii) uricosuric agents, e.g., probenecid,sulfinpyrazone, and benzbromarone; (xiii) growth hormone secretagogues;(xiv) transforming growth factor (TGFβ); (xv) platelet-derived growthfactor (PDGF); (xvi) fibroblast growth factor, e.g., basic fibroblastgrowth factor (bFGF); (xvii) granulocyte macrophage colony stimulatingfactor (GM-CSF); (xviii) capsaicin cream; (xix) Tachykinin NK.sub1. andNK.sub3. receptor antagonists selected from the group consisting ofNKP-608C; SB-233412 (talnetant); and D-4418; (xx) elastase inhibitorsselected from the group consisting of UT-77 and ZD-0892; (xxi) TNF?converting enzyme inhibitors (TACE); (xxii) induced nitric oxidesynthase inhibitors (iNOS) or (xxiii) chemoattractantreceptor-homologous molecule expressed on TH2 cells, (CRTH2antagonists).

A compound of the Formula I may also be used in combination withosteoporosis agents such as roloxifene, droloxifene, lasofoxifene orfosomax and immunosuppressant agents such as FK-506, rapamycin,cyclosporine, azathioprine, and methotrexate.

A compound of the Formula I may also be used in combination withexisting therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as celecoxib,valdecoxib, rofecoxib and etoricoxib, analgesics and intraarticulartherapies such as corticosteroids and hyaluronic acids such as hyalganand synvisc and P2X7 receptor antagonists.

A compound of the Formula I can also be used in combination withexisting therapeutic agents for the treatment of cancer. Suitable agentsto be used in combination include:

(i) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan and nitrosoureas); antimetabolites (for exampleantifolates such as fluoropyrimidines like 5-fluorouracil and tegafur,raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea,gemcitabine and paclitaxel (Taxol®); antitumour antibiotics (for exampleanthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);antimitotic agents (for example vinca alkaloids like vincristine,vinblastine, vindesine and vinorelbine and taxoids like taxol andtaxotere); and topoisomerase inhibitors (for example epipodophyllotoxinslike etoposide and teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordown regulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progestogens (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;(iii) Agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function);(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbb2 antibody trastuzumab [Herceptin™] and theanti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors,tyrosine kinase inhibitors and serine/threonine kinase inhibitors, forexample inhibitors of the epidermal growth factor family (for exampleEGFR family tyrosine kinase inhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in International Patent ApplicationsWO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds thatwork by other mechanisms (for example linomide, inhibitors of integrinαvβ3 function and angiostatin);(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO00/40529,WO 00/41669, WO01/92224, WO02/04434 and WO02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

If formulated as a fixed dose such combination products employ acompound of the Formula I within the dosage range described herein andthe other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

Although a compound of the Formula I is primarily of value as atherapeutic agent for use in warm-blooded animals (including man), it isalso useful whenever it is required to inhibit the effects of cytokines.Thus, it is useful as pharmacological standard for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

The invention will now be illustrated in the following non-limitingExample in which, unless otherwise stated:—

(i) operations were carried out at ambient temperature, i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such as argonunless otherwise stated;

(ii) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany or high pressure liquidchromatography (HPLC) was performed on C18 reverse phase silica, forexample on a Dynamax C-18 60 Å preparative reversed-phase column;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the structure of a compound of the Formula I of the invention wasconfirmed by nuclear magnetic resonance (NMR) and mass spectraltechniques; fast-atom bombardment (FAB) mass spectral data were obtainedusing a Platform spectrometer and, where appropriate, either positiveion data or negative ion data were collected; NMR chemical shift valueswere measured on the delta scale [proton magnetic resonance spectra weredetermined using a Varian Gemini 2000 spectrometer operating at a fieldstrength of 300 MHz or a Bruker AM250 spectrometer operating at a fieldstrength of 250 MHz]; the following abbreviations have been used: s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;

(vi) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; and

(vii) the following abbreviations have been used:—

DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DCM dichloromethaneDMSO dimethylsulphoxide THF tetrahydrofuran HATUO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate DIPEA N,N′-diisopropylethylamine HOBT1-hydroxybenzotriazole hydrate EDAC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

EXAMPLE 13-{[4-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide

To a solution of 4-benzyloxybenzoic acid (11.0 g, 48 mmol) in DCM (100mL) at 0° C. was added oxalyl chloride (8.4 mL, 96 mmol) followed by DMF(two drops). The resulting mixture was stirred at room temperature for 2hours. The mixture was evaporated giving a white solid which wasdissolved in DCM (50 mL). The resulting solution was added portionwiseto a stirred solution of 3-amino-N-cyclopropyl-4-methylbenzamide (7.61g, 40 mmol) and pyridine (7.76 mL, 96 mmol) in DCM (100 mL) at 0° C. Theresulting mixture was stirred at room temperature for 2 hours. The solidwas collected by filtration and washed three times with DCM to give thetitle compound as a white solid (13.9 g, 87%); NMR Spectrum: (DMSOd₆)0.60 (m, 4H), 2.25 (s, 3H), 2.84 (m, 1H), 5.20 (s, 2H), 7.14 (d, 2H),7.39 (m, 6H), 7.63 (d, 1H), 7.79 (s, 1H), 7.97 (d, 2H), 8.37 (s, 1H),9.82 (s, 1H); Mass Spectrum: M+H⁺ 399.

The 3-amino-N-cyclopropyl-4-methylbenzamide used as starting materialwas prepared as follows:—

A) To a stirred solution of 4-methyl-3 nitrobenzoyl chloride (20 g) inmethylene chloride (200 mL) at 0° C. was added a mixture ofcyclopropylamine (7.62 mL) and triethylamine (28 mL). The mixture wasallowed to warm to room temperature and stirred for a further 16 hours.The reaction mixture was evaporated in vacuo and a saturated aqueoussolution of sodium bicarbonate was added. The precipitated solid wasfiltered off and washed with isohexane and dried (magnesium sulphate) togive N-cyclopropyl-4-methyl-3-nitrobenzamide as a colourless solid (22.9g); NMR Spectrum: (DMSOd₆) 0.60 (m, 2H), 0.72 (m, 2H), 2.56 (s, 3H),2.87 (m, 1H), 7.60 (d, 1H), 8.06 (m, 1H), 8.41 (d, 1H), 8.67 (d, 1H);Mass Spectrum: M+H⁺ 221.B) A suspension of N-cyclopropyl-4-methyl-3-nitrobenzamide (22.92 g) and10% palladium on carbon (2 g) in absolute alcohol (500 mL) was agitatedunder a hydrogen atmosphere for 16 hours. The reaction mixture wasfiltered through diatomaceous earth (Celite®) and the filtrateevaporated to dryness to give the title compound as a colourless solid(17.1 g); NMR Spectrum: (DMSOd₆) 0.53 (m, 2H), 0.65 (m, 2H), 2.07 (s,3H), 2.80 (m, 1H), 6.92 (m, 2H), 7.06 (d, 1H), 8.09 (d, 1H); MassSpectrum: M+H⁺ 191.

EXAMPLE 2

Using an analogous procedure to that described in Example 1, theappropriate starting material was reacted with oxalyl chloride followedby 3-amino-N-cyclopropyl-4-methylbenzamide to give the compoundsdescribed in Table 1.

TABLE 1

R³ R⁴ Method Note Benzyloxy H Ex 1 a Methoxy Benzyloxy Ex 1 b MethylBenzyloxy Ex 1 c Fluoro Benzyloxy Ex 1 d Notes a The product gave thefollowing data; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.29(s, 3H), 2.86 (m, 1H), 5.22 (s, 2H), 7.25 (m, 1H), 7.42 (m, 7H), 7.62(m, 2H), 7.83 (s, 1H), 8.41 (s, 1H), 9.99 (s, 1H); Mass Spectrum: M − H⁻399. b The product gave the following data; NMR Spectrum: (DMSOd₆) 0.57(m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.86 (m, 1H), 3.86 (m, 3H), 5.22(s, 2H), 7.17 (m, 1H), 7.41 (m, 6H), 7.63 (m, 3H), 7.79 (m, 1H), 8.37(m, 1H), 9.86 (s, 1H); Mass Spectrum: M − H⁻ 429. The4-(benzyloxy)-3-methoxybenzoic acid used as starting material wasprepared as follows:-To a stirred solution of 4-hydroxy-3-methoxybenzoicacid (5 g, 30 mmol) in THF (15 mL) was added a solution of sodiumhydroxide (3 g) in water (37.5 mL). The resulting mixture was cooled to0° C. and a solution of benzyl chloride (4.1 mL, 34.8 mmol) in THF (15mL) was added. The resulting mixture was allowed to warm to roomtemperature then heated to 70° C. for 18 hours then to 90° C. for 4hours. The mixture was cooled and evaporated. The residual aqueousmixture was washed with isohexane then acidified with 2M hydrochloricacid solution. The resulting precipitate was collected by filtration,washed with isohexane and dried giving the title compound (5.76 g, 74%);NMR Spectrum: (DMSOd₆) 3.83 (s, 3H), 5.19 (s, 2H), 7.14 (m, 1H), 7.40(m, 6H), 7.55 (dd, 1H), 12.69 (m, 1H); Mass Spectrum: M − H⁻ 257. c Theproduct gave the following data; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H),0.68 (m, 2H), 2.26 (m, 6H), 2.85 (m, 1H), 5.27 (s, 2H), 7.15 (m, 1H),7.34 (m, 2H), 7.42 (m, 2H), 7.50 (m, 2H), 7.63 (m, 1H), 7.78 (m, 1H),7.85 (m, 2H), 8.40 (m, 1H), 9.84 (s, 1H); Mass Spectrum: M + H⁺ 415. dThe product gave the following data; NMR Spectrum: (DMSOd₆) 0.57 (m,2H), 0.68 (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 5.32 (s, 2H), 7.42 (m,7H), 7.65 (dd, 1H), 7.83 (m, 3H), 8.41 (d, 1H), 9.97 (s, 1H)); MassSpectrum: M + H⁺ 419. The 4-(benzyloxy)-3-fluorobenzoic acid used asstarting material was prepared from 4-hydroxy-3-fluorobenzoic acid usingan analogous procedure to that used to prepare4-(benzyloxy)-3-methoxybenzoic acid; NMR Spectrum: (DMSOd₆) 5.24 (s,2H), 7.21 (m, 1H), 7.45 (m, 5H), 7.71 (m, 2H); Mass Spectrum: M − H⁻245.

EXAMPLE 34-(benzyloxy)-3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}benzamide

To a solution of 4-(benzyloxy)-3-chlorobenzoic acid (1.5 g, 5.73 mmol)in DMF (11.5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2.2 g, 11.5 mmol), hydroxybenztriazole (1.55 g, 11.5mmol) and N-methyl-morpholine (2.28 mL) followed by3-amino-N-cyclopropyl-4-methylbenzamide (1.09 g, 5.73 mmol). Theresulting mixture was stirred at room temperature for 48 hours. Themixture was evaporated. A saturated aqueous solution of potassiumcarbonate was added, the resulting precipitate was collected byfiltration, washed with dilute hydrochloric acid then saturated aqueouspotassium carbonate solution, then triturated with diethyl ether givingthe title compound as a solid (2.0 g, 81%); NMR Spectrum: (DMSOd₆) 0.57(m, 2H), 0.69 (m, 2H), 2.27 (s, 3H), 2.85 (m, 1H), 5.35 (s, 2H), 7.39(m, 5H), 7.51 (m, 2H), 7.65 (m, 1H), 7.78 (m, 1H), 7.97 (m, 1H), 8.10(m, 1H), 8.40 (m, 1H), 10.01 (s, 1H); Mass Spectrum: M+H⁺ 435.

The 4-(benzyloxy)-3-chlorobenzoic acid used as starting material wasprepared from 4-hydroxy-3-chlorobenzoic acid using an analogousprocedure to that used to prepare 4-(benzyloxy)-3-methoxybenzoic acid(paragraph (b) in the Notes section of Example 2). NMR Spectrum:(DMSOd₆) 5.21 (s, 2H), 7.14 (d, 1H), 7.34 (m, 1H), 7.41 (m, 2H), 7.48(m, 2H), 7.80 (dd, 1H), 7.92 (d, 1H); Mass Spectrum: M−H⁻ 261.

EXAMPLE 4N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide

To a stirred solution ofN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (500 mg,1.61 mmol) in DMF (2.5 mL) was added potassium carbonate (446 mg, 3.22mmol). The resulting mixture was stirred at room temperature for 15minutes. 2-Chloromethyl-pyridine hydrochloride (291 mg, 1.78 mmol) wasadded and the resulting mixture stirred and heated to 50° C. for 18 h.The mixture was cooled to room temperature and saturated aqueouspotassium carbonate solution (15 mL) and ethyl acetate (5 mL) wereadded. The resulting mixture was stirred for 20 minutes. The solid wascollected by filtration, washed with saturated aqueous potassiumcarbonate solution, ethyl acetate and isohexane and dried giving thetitle compound as a solid (425 mg, 60%); NMR Spectrum: (DMSOd₆) 0.56 (m,2H), 0.68 (m, 2H), 2.29 (s, 3H), 2.86 (m, 1H), 5.33 (s, 2H), 7.16 (m,2H), 7.34 (m, 2H), 7.55 (m, 1H), 7.62 (m, 1H), 7.81 (s, 1H), 7.86 (m,1H), 7.98 (m, 2H), 8.36 (s, 1H), 8.60 (m, 1H), 10.00 (s, 1H); MassSpectrum: M+H⁺ 401.

The N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide used asstarting material was prepared as follows:—

To a stirred solution of3-{[4-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (11.5 g,28.8 mmol) in methanol (250 mL) was added 10% palladium on carbon (1.1g) under argon. The argon atmosphere was replaced with hydrogen(balloon) and the resulting mixture stirred at room temperature for 18h. The mixture was filtered through diatomaceous earth (Celite®) and thefiltrate evaporated to dryness to give the title compound as acolourless solid (8.26 g, 92%); NMR Spectrum: (DMSOd₆) 0.57 (m, 2H),0.68 (m, 2H), 2.28 (s, 3H), 2.86 (m, 1H), 6.87 (m, 2H), 7.32 (m, 1H),7.62 (m, 1H), 7.81 (s, 1H), 7.88 (m, 2H), 8.36 (m, 1H), 9.74 (s, 1H),10.31 (s, 1H); Mass Spectrum: M−H⁻ 309.

EXAMPLE 5

Using an analogous procedure to that described in Example 4, theappropriate starting materials were reacted to give the compoundsdescribed in Table 2.

TABLE 2

R³ R⁴ Method Note H 1,3-thiazol-4-ylmethoxy Ex 4 a H pyridin-3-ylmethoxyEx 4 b H (5-methylisoxazol-3- Ex 4 c yl)methoxy H(5-chloro-1,2,3-thiadiazol-4- Ex 4 d yl)methoxy Himidazo[1,2-a]pyridin-2- Ex 4 e ylmethoxy H (2-methyl-1,3-thiazol-4- Ex4 f yl)methoxy H (3,5-dimethylisoxazol-4- Ex 4 g yl)methoxy H1,2,5-thiadiazol-3-ylmethoxy Ex 4 h H (2-carbomethoxy-furan-5- Ex 4 iyl)methoxy H (2-chloro-1,3-thiazol-5- Ex 4 j yl)methoxy1,3-thiazol-4-ylmethoxy H Ex 4 k (2-methyl-1,3-thiazol-4- H Ex 4 lyl)methoxy pyridin-2-ylmethoxy H Ex 4 m (3,5-dimethylisoxazol-4- H Ex 4n yl)methoxy 1,2,5-thiadiazol-3- H Ex 4 o ylmethoxy(2-chloro-1,3-thiazol-5- H Ex 4 p yl)methoxy Methoxy pyridin-2-ylmethoxyEx 4 q Methoxy 1,3-thiazol-4-ylmethoxy Ex 4 r Methyl pyridin-2-ylmethoxyEx 4 s Methyl 1,3-thiazol-4-ylmethoxy Ex 4 t Methyl(2-methyl-1,3-thiazol-4- Ex 4 u yl)methoxy Methyl(3,5-dimethylisoxazol-4- Ex 4 v yl)methoxy Methyl1,2,5-thiadiazol-3-ylmethoxy Ex 4 w Methyl (2-carbomethoxy-furan-5- Ex 4x yl)methoxy Fluoro pyridin-2-ylmethoxy Ex 4 y Fluoro(2-methyl-1,3-thiazol-4- Ex 4 z yl)methoxy Fluoro(3,5-dimethylisoxazol-4- Ex 4 aa yl)methoxy Fluoro1,2,5-thiadiazol-3-ylmethoxy Ex 4 ab Fluoro 1,3-thiazol-4-ylmethoxy Ex 4ac Fluoro imidazo[1,2-a]pyridin-2- Ex 4 ad ylmethoxy Chloropyridin-2-ylmethoxy Ex 4 ae Chloro 1,3-thiazol-4-ylmethoxy Ex 4 af H5-cyclopropyl-1,3,4- Ex 4 ag thiadiazol-2-ylmethoxy H6-bromopyridin-2-ylmethoxy Ex 4 ah H 6-methylpyridin-2-ylmethoxy Ex 4 aiH 4-methanesulfonylbenzyloxy Ex 4 aj H 6-methoxycarbonylpyridin-2- Ex 4ak ylmethoxy Notes a The product gave the following data; NMR Spectrum:(DMSOd₆) 0.58 (m, 2H), 0.68 (m, 2H), 2.30 (s, 3H), 2.85 (m, 1H), 5.37(s, 2H), 7.18 (m, 2H), 7.33 (m, 1H), 7.64 (m, 1H), 7.83 (m, 2H), 7.99(m, 2H), 8.39 (m, 1H), 9.17 (s, 1H), 9.90 (s, 1H); Mass Spectrum: M −H⁻406. b The product gave the following data; NMR Spectrum: (DMSOd₆)0.58 (m, 2H), 0.69 (m, 2H), 2.30 (s, 3H), 2.86 (m, 1H), 5.31 (s, 2H),7.17 (m, 2H), 7.33 (m, 1H), 7.45 (m, 1H), 7.63 (m, 1H), 7.83 (s, 1H),7.91 (m, 1H), 8.00 (m, 2H), 8.36 (m, 1H), 8.57 (m, 1H), 8.71 (m, 1H),9.85 (s, 1H); Mass Spectrum: M + H⁺ 402. c The product gave thefollowing data; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.28(s, 3H), 2.44 (s, 3H), 2.85 (m, 1H), 5.28 (s, 2H), 6.37 (s, 1H), 7.15(m, 2H), 7.31 (m, 1H), 7.60 (m, 1H), 7.82 (s, 1H), 7.99 (m, 2H), 8.41(s, 1H), 10.40 (s, 1H); Mass Spectrum: M − H⁻ 404. d The product gavethe following data; NMR Spectrum: (DMSOd₆) 0.58 (m, 2H), 0.68 (m, 2H),2.29 (s, 3H), 2.86 (m, 1H), 5.62 (s, 2H), 7.24 (m, 2H), 7.34 (m, 1H),7.64 (m, 1H), 7.83 (s, 1H), 8.01 (m, 2H), 8.37 (m, 1H), 9.95 (s, 1H);Mass Spectrum: M − H⁻ 441. e The product gave the following data; NMRSpectrum: (DMSOd₆) 0.56 (m, 2H), 0.66 (m, 2H), 2.27 (s, 3H), 2.84 (m,1H), 5.32 (s, 2H), 6.89 (m, 1H), 7.24 (m, 4H), 7.56 (m, 2H), 7.81 (s,1H), 7.98 (m, 3H), 8.38 (m, 1H), 8.53 (m, 1H), 9.94 (s, 1H); MassSpectrum: M + H⁺ 441. f The product gave the following data; NMRSpectrum: (DMSOd₆) 0.56 (m, 2H), 0.67 (m, 2H), 2.28 (s, 3H), 2.68 (s,3H), 2.84 (m, 1H), 5.21 (s, 2H), 7.15 (m, 2H), 7.32 (m, 1H), 7.61 (m,2H), 7.81 (s, 1H), 7.97 (d, 2H), 8.37 (m, 1H), 9.88 (s, 1H); MassSpectrum: M + H⁺ 422. g The product gave the following data; NMRSpectrum: (DMSOd₆) 0.58 (m, 2H), 0.69 (m, 2H), 2.25 (s, 3H), 2.26 (m,3H), 2.45 (s, 3H), 2.85 (m, 1H), 5.04 (s, 2H), 7.15 (d, 2H), 7.34 (d,1H), 7.64 (m, 1H), 7.82 (s, 1H), 8.00 (d, 2H), 8.37 (m, 1H), 9.85 (s,1H); Mass Spectrum: M + H⁺ 420. h The product gave the following data;NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.29 (s, 3H), 2.86(m, 1H), 5.58 (s, 2H), 7.20 (d, 2H), 7.34 (d, 1H), 7.64 (m, 1H), 7.82(s, 1H), 8.00 (d, 2H), 8.37 (d, 1H), 9.01 (s, 1H), 9.87 (s, 1H); MassSpectrum: M − H⁻ 407. i The product gave the following data; NMRSpectrum: (DMSOd₆) 0.58 (m, 2H), 0.69 (m, 2H), 2.29 (s, 3H), 2.86 (m,1H), 3.85 (s, 3H), 5.30 (s, 2H), 6.84 (d, 1H), 7.18 (d, 2H), 7.33 (m,2H), 7.64 (m, 1H), 7.82 (s, 1H), 7.99 (d, 2H), 8.37 (m, 1H), 9.88 (s,1H); Mass Spectrum: M − H⁻ 447. j The product gave the following data;NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.86(m, 1H), 5.47 (s, 2H), 7.17 (d, 2H), 7.34 (d, 1H), 7.64 (d, 1H), 7.80(m, 1H), 7.85 (m, 1H), 7.99 (m, 2H), 8.37 (m, 1H), 9.87 (s, 1H); MassSpectrum: M − H⁻ 440. k The product gave the following data; NMRSpectrum: (DMSOd₆) 0.58 (m, 2H), 0.69 (m, 2H), 2.29 (s, 3H), 2.86 (m,1H), 5.34 (s, 2H), 7.29 (m, 1H), 7.35 (m, 1H), 7.47 (m, 1H), 7.60 (m,1H), 7.66 (m, 2H), 7.82 (m, 2H), 8.38 (m, 1H), 9.15 (m, 1H), 9.99 (s,1H); Mass Spectrum: M + H⁺ 408. TheN-cyclopropyl-3-[(3-hydroxybenzoyl)amino]-4-methylbenzamide used asstarting material was prepared from3-{[3-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide using ananalogous procedure to that used to prepareN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (Methodsection of Example 4). The product gave the following data; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.26 (s, 3H), 2.86 (m,1H), 6.99 (dd, 1H), 7.37 (dd, 4H), 7.64 (dd, 1H), 7.80 (d, 1H), 8.37 (d,1H), 9.80 (d, 2H); Mass Spectrum: M − H⁻ 309. l The product gave thefollowing data; NMR Spectrum: (DMSOd₆) 0.58 (m, 2H), 0.69 (m, 2H), 2.29(s, 3H), 2.67 (m, 3H), 2.86 (m, 1H), 5.22 (s, 2H), 7.27 (m, 1H), 7.35(m, 1H), 7.46 (m, 1H), 7.58 (m, 2H), 7.65 (m, 2H), 7.81 (m, 1H), 8.38(m, 1H), 9.99 (s, 1H); Mass Spectrum: M + H⁺ 422. m The product gave thefollowing data; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.29(s, 3H), 2.86 (m, 1H), 5.30 (s, 2H), 7.27 (m, 1H), 7.36 (m, 2H), 7.47(m, 1H), 7.61 (m, 4H), 7.81 (m, 1H), 7.86 (m, 1H), 8.38 (m, 1H), 8.60(m, 1H), 9.98 (m, 1H); Mass Spectrum: M + H⁺ 402. n The product gave thefollowing data; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.25(s, 3H), 2.27 (s, 3H), 2.44 (s, 3H), 2.86 (m, 1H), 5.02 (s, 2H), 6.90(s, 1H), 7.24 (m, 1H), 7.35 (d, 1H), 7.47 (t, 1H), 7.63 (m, 2H), 7.80(d, 1H), 8.38 (d, 1H), 9.97 (s, 1H); Mass Spectrum: M + H⁺ 442. o Theproduct gave the following data; Mass Spectrum: M − H⁻ 407. p Theproduct gave the following data; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H),0.69 (m, 2H), 2.27 (s, 3H), 2.86 (m, 1H), 5.46 (s, 2H), 7.27 (dd, 1H),7.35 (d, 1H), 7.48 (m, 1H), 7.64 (m, 3H), 7.82 (m, 2H), 8.38 (d, 1H),9.98 (s, 1H); Mass Spectrum: M + H⁺ 409. q The product gave thefollowing data NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.27(s, 3H), 2.86 (m, 1H), 3.90 (s, 3H), 5.29 (s, 2H), 7.17 (d, 1H), 7.36(m, 2H), 7.59 (m, 4H), 7.79 (m, 1H), 7.87 (m, 1H), 8.42 (m, 1H), 8.60(m, 1H), 9.98 (s, 1H); Mass Spectrum: M + H⁺ 432. TheN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-hydroxy-3-methoxybenzamideused as starting material was prepared from4-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methoxybenzamideusing an analogous procedure to that used to prepareN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4- methylbenzamide (Methodssection of Example 4). The product gave the following data; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.86 (m,1H), 3.85 (s, 3H), 6.88 (d, 1H), 7.33 (d, 1H), 7.52 (dd, 1H), 7.57 (d,1H), 7.64 (dd, 1H), 7.79 (d, 1H), 8.36 (d, 1H), 9.63 (s, 1H), 9.74 (s,1H); Mass Spectrum: M + H⁺ 341. r The product gave the following data;NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.28 (s, 3H), 2.86(m, 1H), 3.87 (s, 3H), 5.32 (s, 2H), 7.25 (d, 1H), 7.33 (m, 1H), 7.62(m, 3H), 7.81 (m, 2H), 8.42 (m, 1H), 9.16 (m, 1H), 10.04 (s, 1H); MassSpectrum: M + H⁺ 438. s The product gave the following data; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.35 (s,3H), 2.86 (m, 1H), 5.33 (s, 2H), 7.14 (m, 1H), 7.35 (m, 2H), 7.56 (m,2H), 7.64 (m, 2H), 7.83 (m, 4H), 8.36 (m, 1H), 8.61 (m, 1H), 9.81 (s,1H); Mass Spectrum: M + H⁺ 416. TheN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-hydroxy-3-methylbenzamideused as starting material was prepared from4-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methylbenzamideusing an analogous procedure to that used to prepareN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4- methylbenzamide (Methodssection of Example 4). The product gave the following data; NMRSpectrum: (DMSOd₆) 0.56 (m, 2H), 0.68 (m, 2H), 2.21 (s, 3H), 2.27 (s,3H), 2.85 (d, 1H), 6.87 (m, 1H), 7.32 (m, 1H), 7.62 (m, 1H), 7.70 (m,1H), 7.79 (s, 2H), 8.40 (m, 1H), 9.72 (s, 1H), 10.02 (s, 1H); MassSpectrum: M + H⁺ 325. t The product gave the following data; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.26 (m, 6H), 2.86 (m,1H), 5.38 (s, 2H), 7.24 (m, 1H), 7.33 (m, 1H), 7.63 (m, 1H),7.83 (m,4H), 8.37 (m, 1H), 9.15 (m, 1H), 9.84 (s, 1H); Mass Spectrum: M + H⁺422. u The product gave the following data; NMR Spectrum: (DMSOd₆) 0.57(m, 2H), 0.68 (m, 2H), 2.24 (m, 6H), 2.68 (m, 3H), 2.86 (m, 1H), 5.25(s, 2H), 7.22 (m, 1H), 7.33 (m, 1H), 7.59 (s, 1H), 7.64 (m, 1H), 7.79(m, 1H), 7.85 (m, 2H), 8.40 (m, 1H), 9.85 (s, 1H); Mass Spectrum: M + H⁺436. v The product gave the following data; NMR Spectrum: (DMSOd₆) 0.57(m, 2H), 0.70 (m, 2H), 2.22 (s, 3H), 2.28 (s, 6H), 2.46 (s, 3H), 2.85(m, 1H), 5.06 (s, 2H), 7.19 (m, 1H), 7.34 (m, 1H), 7.64 (m, 1H), 7.85(m, 3H), 8.43 (m, 1H), 9.84 (m, 1H); Mass Spectrum: M + H⁺ 434. w Theproduct gave the following data; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H),0.68 (m, 2H), 2.27 (s, 3H), 2.31 (s, 3H), 2.85 (m, 1H), 5.60 (s, 2H),7.20 (m, 1H), 7.33 (m, 1H), 7.63 (m, 1H), 7.79 (m, 1H), 7.86 (m, 2H),8.41 (m, 1H), 9.03 (s, 1H), 9.87 (s, 1H); Mass Spectrum: M + H⁺ 423 xThe product gave the following data; NMR Spectrum: (DMSOd₆) 0.57 (m,2H), 0.69 (m, 2H), 2.23 (s, 3H), 2.25 (m, 3H), 2.85 (m, 1H), 3.81 (m,3H), 5.31 (s, 2H), 6.84 (m, 1H), 7.24 (m, 1H), 7.33 (m, 2H), 7.64 (m,1H), 7.78 (m, 1H), 7.86 (m, 2H), 8.40 (m, 1H), 9.87 (s, 1H); MassSpectrum: M + H⁺ 463. y The product gave the following data; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.28 (s, 3H), 2.86 (m,1H), 5.41 (s, 2H), 7.38 (m, 3H), 7.56 (m, 1H), 7.64 (m, 1H), 7.84 (m,4H), 8.40 (m, 1H), 8.61 (m, 1H), 10.04 (m, 1H); Mass Spectrum: M + H⁺420. TheN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-hydroxybenzamideused as starting material was prepared from4-(benzyloxy)-3-fluoro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}benzamideusing an analogous procedure to that used to prepareN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (Methodssection of Example 4). The product gave the following data; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.28 (s, 3H), 2.85 (m,1H), 7.08 (m, 1H), 7.33 (m, 1H), 7.64 (m, 1H), 7.72 (m, 1H), 7.80 (m,2H), 8.37 (m, 1H), 9.84 (s, 1H), 10.60 (m, 1H); Mass Spectrum: M − H⁻327. z The product gave the following data; NMR Spectrum: (DMSOd₆) 0.57(m, 2H), 0.68 (m, 2H), 2.28 (s, 3H), 2.67 (m, 4H), 2.85 (m. 1H). 5.31(s, 2H), 7.35 (m, 1H), 7.48 (m, 1H), 7.65 (m, 2H), 7.80 (s, 1H), 7.86(m, 2H), 9.99 (s, 1H); Mass Spectrum: M + H⁺ 440. aa The product gavethe following data; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H),2.28 (s, 6H), 2.46 (s, 3H), 2.86 (m, 1H), 5.15 (s, 2H), 7.34 (d, 1H),7.44 (t, 1H), 7.64 (m, 1H), 7.80 (m, 1H), 7.87 (m, 2H), 8.37 (m, 1H),9.95 (m, 1H); Mass Spectrum: M + H⁺ 438. ab The product gave thefollowing data; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.28(s, 3H), 2.85 (m, 1H), 5.68 (s, 2H), 7.35 (m, 1H), 7.47 (m, 1H), 7.65(m, 1H), 7.81 (s, 1H), 7.87 (m, 2H), 8.37 (m, 1H), 9.01 (s, 1H), 9.97(s, 1H); Mass Spectrum: M − H⁻ 425. ac The product gave the followingdata; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H),2.86 (m, 1H), 5.44 (s, 2H), 7.34 (m, 1H), 7.50 (m, 1H), 7.65 (m, 1H),7.79 (m, 1H), 7.86 (m, 3H), 8.37 (m, 1H), 9.16 (m, 1H), 9.94 (m, 1H);Mass Spectrum: M − H⁻ 424. ad The product gave the following data; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.26 (s, 3H), 2.86 (m,1H), 5.40 (s, 2H), 6.91 (td, 1H), 7.27 (ddd, 1H), 7.34 (m, 1H), 7.55 (t,2H), 7.65 (dd, 1H), 7.79 (d, 1H), 7.85 (m, 2H), 8.08 (s, 1H), 8.37 (d,1H), 8.55 (m, 1H), 9.91 (s, 1H); Mass Spectrum: M + H⁺ 459 ae Theproduct gave the following data; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H),0.68 (m, 2H), 2.27 (s, 3H), 2.86 (m, 1H), 5.42 (s, 2H), 7.33 (m, 1H),7.39 (m, 2H), 7.61 (m, 2H), 7.79 (m, 1H), 7.89 (m, 1H), 7.97 (m, 1H),8.12 (m, 1H), 8.36 (m, 1H), 8.61 (m, 1H), 9.98 (m, 1H); Mass Spectrum:M + H⁺ 436. The3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-hydroxybenzamideused as starting material was prepared from4-(benzyloxy)-3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}benzamideusing an analogous procedure to that used to prepareN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (Methodssection of Example 4) except that ethyl acetate was used as the solventin place of methanol. The product gave the following data; NMR Spectrum:(DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.86 (m, 1H), 7.08(m, 1H), 7.33 (m, 1H), 7.64 (m, 1H), 7.80 (m, 2H), 8.03 (m, 1H), 8.36(m, 1H), 9.87 (s, 1H), 10.79 (m, 1H); Mass Spectrum: M − H⁻ 343. af Theproduct gave the following data; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H),0.68 (m, 2H), 2.28 (s, 3H), 2.86 (m, 1H), 5.46 (s, 2H), 7.33 (d, 1H),7.48 (d, 1H), 7.62 (dd, 1H), 7.79 (d, 1H), 7.86 (d, 1H), 7.98 (dd, 1H),8.10 (d, 1H), 8.36 (d, 1H), 9.16 (d, 1H), 9.98 (s, 1H); Mass Spectrum: M− H⁻ 424. ag The product gave the following data: NMR Spectrum: (DMSOd₆)0.57 (m, 2H), 0.68 (m, 2H), 1.04 (m, 2H), 1.23 (m, 2H), 2.33 (s, 3H),2.85 (m, 1H), 5.68 (s, 1H), 5.77 (s, 1H), 7.20 (d, 2H), 7.34 (d, 1H),7.64 (d, 1H), 7.80 (s, 1H), 7.98 (d, 2H), 8.41 (d, 1H), 8.42 (s, 1H),9.90 (s, 1H); Mass Spectrum: M + H⁺ 449. ah The product gave thefollowing data: NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.26(s, 3H), 2.86 (m, 1H), 5.29 (s, 2H), 7.18 (d, 2H), 7.33 (d, 1H), 7.59(m, 1H), 7.64 (m, 2H), 7.82 (m, 2H), 8.00 (m, 2H), 8.37 (m, 1H), 9.86(s, 1H); Mass Spectrum: M + H⁺ 482. ai The product gave the followingdata: NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.26 (s, 3H),2.86 (m, 1H), 5.23 (s, 2H), 7.16 (d, 2H), 7.23 (d, 1H), 7.33 (m, 2H),7.64 (m, 1H), 7.73 (m, 1H), 7.80 (d, 1H), 8.37 (m, 1H), 9.83 (s, 1H);Mass Spectrum: M + H⁺ 416. aj The product gave the following data: NMRSpectrum: (DMSOd₆) 0.62 (m, 2H), 0.85 (m, 2H) 2.40 (s, 3H), 2.88 (m,1H), 3.07 (s, 3H), 5.25 (s, 1H), 6.40 (s, 1H), 7.08 (d, 2H), 7.28 (m,1H), 7.62 (d, 1H), 7.65 (d, 2H), 7.70 (s, 1H), 7.88 (d, 2H), 7.98 (d,2H), 8.40 (s, 1H); Mass Spectrum: M + Na⁺ 501. ak The product gave thefollowing data: NMR Spectrum: (DMSOd₆) 0.56 (m, 2H), 0.68 (m, 2H), 2.24(s, 3H), 2.84 (m, 1H), 5.38 (s, 2H), 7.16 (d, 2H), 7.31 (d, 1H), 7.62(dd, 1H), 7.69 (d, 1H), 7.98 (d, 2H), 8.35 (m, 2H), 9.09 (s, 1H), 9.82(s, 1H); Mass spectrum: M + H⁺ 460. The methyl 2-chloromethylnicotinateused as starting material was prepared according to Chem. Ber. (1987)120, 649.

EXAMPLE 6N-cyclopropyl-3-({4-[(4-methoxypyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide

To a stirred solution ofN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (200 mg,0.64 mmol) and 4-methoxy-2-hydroxymethylpyridine (500 mg, 3.6 mmol) indry THF (25 mL) under an argon atmosphere was added successivelytributylphosphine (500 mg, 2.5 mmol) and di-isopropyl azodicarboxylate(500 mg, 2.5 mmol). The mixture was stirred at 20° C. for 16 hours, thenthe solvent was evaporated at reduced pressure and the residue purifiedby silica column chromatography, eluting with a gradient of 0 to 10%methanol in ethyl acetate to give the title compound as a white solid(100 mg); NMR Spectrum: (DMSOd₆) 1.55 (m, 2H), 1.65 (m, 2H), 2.25 (s,3H), 2.85 (m, 1H), 3.85 (s, 3H), 5.20 (s, 2H), 6.95 (dd, 1H), 7.05 (d,1H), 7.15 (d, 2H), 7.30 (d, 1H), 7.60 (dd, 1H), 7.80 (s, 1H), 7.95 (d,2H), 8.35 (d, 1H), 8.40 (broad s, 1H), 9.80 (s, 1H); Mass Spectrum: M+H⁺432.

The 4-methoxy-2-hydroxymethylpyridine used as starting material wasprepared according to J. Med. Chem. (1995) 38, 4910.

EXAMPLE 7N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,5-difluoro-4-(pyridin-2-ylmethoxy)benzamide

A mixture ofN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,4,5-trifluorobenzamide(100 mg, 0.29 mmol), 2-pyridinylmethanol (400 μl) and potassiumt-butoxide (32 mg, 0.29 mmol) in NMP (600 μl) was heated in themicrowave at 180° C. for 1.5 hrs. The reaction mixture was cooled andpartitioned between saturated aqueous sodium bicarbonate and ethylacetate. The organic phase was washed with dilute aqueous citric acid.Evaporation of the ethyl acetate gave impure product which was purifiedon silica column chromatography eluting with 0 to 100% ethyl acetate inisohexane. The solvents were evaporated to give a residue which wasdissolved in ethyl acetate, then extracted with dilute hydrochloricacid. The aqueous extracts were basified with saturated aqueous sodiumbicarbonate solution and then extracted with ethyl acetate to give thetitle compound as a solid (29 mg, 23%); NMR Spectrum: (DMSOd₆) 0.58 (m,2H), 0.69 (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 5.36 (s, 2H), 7.37 (m,2H), 7.64 (m, 2H), 7.84 (m, 4H), 8.40 (m, 1H), 8.56 (m, 1H), 10.14 (s,1H); Mass Spectrum: M−H⁻ 436.

TheN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,4,5-trifluorobenzamideused as starting material was prepared as follows:—

To a solution of 3-amino-N-cyclopropyl-4-methylbenzamide (1.06 g, 5.58mmol) in DMF (11 mL) was added trifluorobenzoic acid (0.983 mg, 5.58mmol), HOBT (1.51 g, 11.2 mmol) and EDAC hydrochloride (2.14 g, 11.2mmol) and the resulting mixture was stirred for 16 h. Saturated aqueoussodium bicarbonate was added and the title compound filtered off (1.70g, 88%).

EXAMPLE 8N-cyclopropyl-4-methyl-3-({4-[(3-methylpyridin-2-yl)methoxy]benzoyl}amino)benzamide

To (3-methylpyridine-2-yl)methanol (157 mg, 1.272 mmol) in DCM (5 mL)was added thionyl chloride (200 μl) and the mixture stirred and heatedat reflux for 4 h. The mixture was evaporated to dryness. To the residuewas added N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide(197 mg, 0.636 mmol) and potassium carbonate (176 mg, 1.27 mmol) inacetonitrile (5 mL) and the resulting mixture heated at 80° C. for 16 h.The reaction mixture was cooled and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. The organic phase wasconcentrated under reduced pressure. Precipitation with DCM in diethylether gave the title compound as a solid (270 mg); NMR Spectrum:(DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.40 (s, 3H), 2.86(m, 1H), 5.30 (s, 2H), 7.17 (d, 2H), 7.33 (m, 2H), 7.65 (m, 2H), 7.82(s, 1H), 7.97 (d, 2H), 8.39 (m, 2H), 9.81 (s, 1H); Mass Spectrum: M+H⁺416.

EXAMPLE 9N-cyclopropyl-4-methyl-3-{[4-(pyrimidin-2-ylmethoxy)benzoyl]amino}benzamide

The title compound was prepared from 2-pyrimidinemethanol andN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide according tothe method used to prepared Example 8, to give the title compound as asolid (149 mg, 58%); NMR Spectrum: (DMSOd₆) 0.56 (m, 2H), 0.67 (m, 2H),2.24 (s, 3H), 2.84 (m, 1H), 5.37 (s, 2H), 7.09 (d, 2H), 7.31 (d, 1H),7.47 (m, 1H), 7.61 (m, 1H), 7.78 (d, 1H), 7.93 (d, 2H), 8.35 (m, 1H),8.83 (m, 2H), 9.80 (s, 1H); Mass Spectrum: M+H⁺ 403.

EXAMPLE 10N-cyclopropyl-4-methyl-3-{[4-(pyridazin-3-ylmethoxy)benzoyl]amino}benzamide

To a solution of 3-pyridazinylmethanol (140 mg, 1.27 mmol) in DCM (5 mL)was added thionyl chloride (103 μl, 1.42 mmol) and the resulting mixturestirred at room temperature for 4 h. The solvent was evaporated underreduced pressure and then to the residue in DMSO (4 mL) was addedN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (197 mg,0.636 mmol), cesium carbonate (621 mg, 1.91 mmol) and tetrabutylammoniumiodide (235 mg, 0.636 mmol) and the resulting mixture stirred at 60° C.for 16 h. The reaction mixture was added to a 20 g SCX column andproduct eluted with methanol. Concentration under reduced pressure gaveimpure product which was further purified on silica columnchromatography eluting with 0-20% methanol/1% ammonium hydroxide SG 0.88in ethyl acetate. Evaporation and trituration with DCM and diethyl etherand filtration gave the title compound as a solid (15 mg, 5.9%); NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.86 (m,1H), 5.54 (s, 2H), 7.21 (d, 2H), 7.34 (d, 1H), 7.64 (m, 1H), 7.79 (m,2H), 7.86 (m, 1H), 7.99 (m, 2H), 8.37 (m, 1H), 9.24 (m, 1H), 9.86 (s,1H); Mass Spectrum: M−H⁻ 401.

EXAMPLE 11N-cyclopropyl-3-({3-[(4-methoxypyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide

To a stirred solution ofN-cyclopropyl-3-[(3-hydroxybenzoyl)amino]-4-methylbenzamide (200 mg,0.65 mmol) in acetonitrile (50 mL) was added anhydrous potassiumcarbonate (220 mg, 1.59 mmol) and 4-methoxy-2-chloromethyl-pyridinehydrochloride (150 mg, 0.75 mmol). The mixture was stirred at reflux for16 hours, then filtered and the solvent evaporated at reduced pressureto give a gum, which was dissolved in ethyl acetate/methanol (19:1, 20mL) and purified by chromatography on silica, eluting with ethylacetate/methanol (9:1) to give the compound as a white solid (250 mg,90%); NMR Spectrum: (CDCl₃) 0.60 (m, 2H), 0.80 (m, 2H), 2.32 (s, 3H),2.86 (m, 1H), 3.85 (s, 3H), 5.19 (s, 2H), 6.67 (s, 1H), 6.75 (dd, 1H),7.04 (d, 1H), 7.17 (dd, 1H), 7.21 (d, 1H), 7.38 (dd, 1H), 7.48 (d, 1H),7.54 (m, 2H), 8.02 (s, 1H), 8.14 (s, 1H), 8.40 (d, 1H); Mass spectrum:M+H⁺ 432.

The 4-methoxy-2-chloromethyl-pyridine hydrochloride used as startingmaterial was prepared according to J. Med. Chem. (1995) 38, 4913.

EXAMPLE 12N-cyclopropyl-3-({4-[(5-hydroxypyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamidehydrobromide

To a stirred solution ofN-cyclopropyl-4-methyl-3-{[4-(5-benzyloxypyridin-2-ylmethoxy)benzoyl]amino}benzamide(1.0 g, 1.97 mmol) in glacial acetic acid (10 mL) was added a solutionof HBr (48% in acetic acid, 30 mL). After 6 hours at 25° C. the solutionwas diluted with ether (100 mL) and the resultant precipitate filteredoff and dried to give the title compound as a pale yellow solid (610 mg,62%); NMR Spectrum: (DMSOd₆) 0.56 (m, 2H), 0.68 (m, 2H), 2.25 (s, 3H),2.84 (m, 1H), 5.36 (s, 2H), 7.18 (d, 2H), 7.31 (d, 1H), 7.63 (dd, 1H),7.78-7.84 (m, 3H), 8.00 (d, 2H), 8.36 (m, 2H), 9.86 (s, 1H); MassSpectrum: M+H⁺ 418.

TheN-cyclopropyl-4-methyl-3-{[4-(5-benzyloxypyridin-2-ylmethoxy)benzoyl]amino}benzamideused as starting material was prepared from5-benzyloxypyrid-2-ylmethanol (prepared according to J. Med. Chem.(1977), 20, 1261) andN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide according tothe procedure used to prepareN-cyclopropyl-3-[(4-{[5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide(Example 14).

EXAMPLE 13N-cyclopropyl-4-methyl-3-({4-[(1-oxidopyridin-2-yl)methoxy]benzoyl}amino)benzamide

N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide(200 mg, 0.5 mmol) was dissolved in dichloromethane (50 mL) and stirredwhile adding 3-chloroperbenzoic acid (85%, 200 mg). The solution wasstirred for one hour at 25° C., then washed twice with sodiumbicarbonate solution and dried. The solvent was evaporated to give thetitle compound as a white solid (120 mg); NMR Spectrum: (DMSOd₆) 0.56(m, 2H), 0.68 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 5.35 (s, 2H), 7.18(d, 2H), 7.31 (d, 1H), 7.42 (m, 2H), 7.60 (m, 2H), 7.78 (m, 1H), 7.99(d, 2H), 8.36 (m, 2H), 9.84 (s, 1H); Mass Spectrum: M+H⁺ 418.

EXAMPLE 14N-cyclopropyl-3-[(4-{[5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide

To a stirred solution ofN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (3.1 g, 10mmol) in dry THF (200 mL) at 25° C. was added[5-(1,3-dioxolan-2-ylmethoxy)-pyridin-2-yl]methanol (2.4 g, 11 mmol),triphenylphosphine (2.9 g, 11 mmol) and di-tert-butyl azodicarboxylate(2.6 g, 11 mmol). The solution was stirred for 16 hours, then thesolvent was evaporated and the residue dissolved in ethylacetate/methanol (19:1, 50 mL) and purified by chromatography on silica,eluting with a gradient of 5-20% methanol in ethyl acetate, to give thetitle compound as a white solid (3.8 g, 76%). NMR Spectrum: (DMSOd₆)0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 3.85 (m, 2H),3.92 (m, 2H), 4.10 (m, 2H), 5.20 (m, 3H), 7.12 (d, 2H), 7.30 (d, 1H),7.45 (s, 2H), 7.62 (dd, 1H), 7.78 (s, 1H), 7.95 (d, 2H), 8.30 (s, 1H),8.35 (d, 1H), 9.80 (s, 1H); Mass Spectrum: M+H⁺ 504.

The [5-(1,3-dioxolan-2-ylmethoxy)-pyridin-2-yl]methanol used as startingmaterial was prepared as follows:—

To a stirred solution of[5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methyl acetate (6.5 g, 25.7mmol) in ethanol (100 mL) was added sodium hydroxide (1.2 g, 30 mmol)and the mixture refluxed for 1 hour. The solvent was evaporated atreduced pressure and the residue was partitioned between water (100 mL)and ethyl acetate (100 mL). The organic layer was separated, dried andevaporated to give the title compound as a solid (5.4 g, 99%); NMRSpectrum: (DMSOd₆) 3.84 (m, 2H), 3.95 (m, 2H), 4.06 (m, 2H), 4.48 (d,2H), 5.19 (t, 1H), 5.28 (broad t, 1H), 7.37 (m, 2H), 8.18 (s, 1H); MassSpectrum: M+H⁺ 212.

The [5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methyl acetate used asstarting material was prepared as follows:—

A solution of 5-(1,3-dioxolan-2-ylmethoxy)-2-methylpyridine 1-oxide (10g, 47.4 mmol) in acetic anhydride (100 mL) was stirred at reflux for 2hours. The reaction was cooled and the solvent evaporated at reducedpressure. The residue was purified by chromatography on silica elutingwith 50% hexane/ethyl acetate to give an oil (6.8 g, 57%); NMR Spectrum:(CDCl₃) 2.12 (s, 3H), 3.94-4.10 (m, 6H), 5.15 (s, 2H), 5.28 (t, 1H),7.16 (m, 2H), 8.32 (d, 1H); Mass Spectrum: M+H⁺ 254.

The 5-(1,3-dioxolan-2-ylmethoxy)-2-methylpyridine 1-oxide used asstarting material was prepared as follows:—

To a stirred solution of 5-(1,3-dioxolan-2-ylmethoxy)-2-methylpyridine(20 g, 0.1 mole) in dichloromethane (200 mL) was added portionwise3-chloroperbenzoic acid (˜80% peracid, 24 g, 0.11 mole) during 10minutes. The mixture was stirred for 1 hour, washed twice with 2N sodiumhydroxide (100 mL) and the organic layer was dried over anhydrousmagnesium sulphate. Evaporation of the solvent gave the title compoundas a white solid (15.4 g, 73%); NMR Spectrum: (DMSOd₆) 2.24 (s, 3H),3.83 (m, 2H), 3.93 (m, 2H), 4.05 (m, 1H), 5.16 (t, 1H), 6.97 (dd, 1H),7.34 (d, 1H), 8.08 (d, 1H); Mass Spectrum: M+H⁺ 212.

The 5-(1,3-dioxolan-2-ylmethoxy)-2-methylpyridine used as startingmaterial was prepared as follows:—

To a stirred solution of 2-methyl-5-hydroxypyridine (16.0 g, 0.147 mole)in dry DMF (100 mL) at 25° C. was added portionwise sodium hydride (60%dispersion in oil, 6.0 g, 0.15 mole) during 10 minutes. To the mixturewas added 2-bromomethyl-1,3-dioxolane (16.0 mL, 0.154 mole) and theresulting mixture heated at 100° C. for 12 hours, cooled to 25° C. anddiluted with ice/water (400 g). The product was extracted into diethylether (400 mL), dried over anhydrous magnesium sulphate, and the solventevaporated at reduced pressure to give the title compound as an oil (25g, 87%); NMR Spectrum: (CDCl₃) 2.50 (s, 3H), 3.94-4.04 (m, 6H), 5.27 (t,1H), 7.05 (d, 1H), 7.15 (dd, 1H), 8.22 (d, 1H); Mass Spectrum: M+H⁺ 196.

EXAMPLE 15N-cyclopropyl-3-{[4-({5-[2-(dimethylamino)ethoxy]pyridin-2-yl}methoxy)benzoyl]amino}-4-methylbenzamide

To a stirred solution ofN-cyclopropyl-3-[(4-{[5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide(1.0 g, 2 mmol) in methanol (20 mL) was added hydrochloric acid (36%aqueous solution, 10 mL). After 2 hours the solution was basified byaddition of 2N sodium hydroxide (55 mL). The precipitate was filteredoff and dissolved in THF (100 mL), then stirred while adding a solutionof dimethylamine (2M in THF, 2 mL, 4 mmol), titanium isopropoxide (3 mL,10 mmol) and sodium triacetoxyborohydride (2.2 g, 10 mmol). After 16hours the mixture was basified with 2N sodium hydroxide, stirred for 10minutes and the top layer decanted. The lower layer was stirred with THF(50 mL) and decanted again, the combined top layers were dried overmagnesium sulphate. The title compound was isolated by chromatography onsilica, eluting with a gradient of 0-30% methanol in ethyl acetate togive a gum (120 mg); NMR Spectrum: (CDCl₃) 0.60 (m, 2H), 0.83 (m, 2H),2.32 (s, 3H), 2.40 (s, 6H), 2.82 (t, 2H), 2.90 (m, 1H), 4.17 (t, 2H),5.20 (s, 2H), 6.60 (s, 1H), 7.06 (d, 2H), 7.26 (dd, 2H), 7.42 (d, 1H),7.56 (d, 1H), 7.86 (d, 2H), 7.90 (s, 1H), 8.10 (s, 1H), 8.32 (s, 1H);Mass Spectrum: M+H⁺ 489.

EXAMPLE 165-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyridine-2-carboxamide

The title compound was prepared from 5-(benzyloxy)pyridine-2-carboxylicacid and 3-amino-N-cyclopropyl-4-methylbenzamide according to the methoddescribed for Example 1; NMR Spectrum: (DMSOd₆) 0.58 (m, 2H), 0.69 (m,2H), 2.32 (s, 3H), 2.86 (m, 1H), 5.32 (s, 2H), 7.39 (m, 4H), 7.51 (m,2H), 7.57 (m, 1H), 7.71 (m, 1H), 8.13 (m, 1H), 8.22 (m, 1H), 8.36 (m,1H), 8.48 (s, 1H), 10.16 (s, 1H); Mass Spectrum: M+Na⁺ 424.

EXAMPLE 17N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)pyridine-2-carboxamide

The title compound was prepared fromN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-hydroxypyridine-2-carboxamideand 2-chloromethyl-pyridine hydrochloride according to the methoddescribed for Example 4; NMR Spectrum: (DMSOd₆) 0.58 (m, 2H), 0.69 (m,2H), 2.32 (s, 3H), 2.86 (m, 1H), 5.40 (s, 2H), 7.33 (m, 1H), 7.39 (m,1H), 7.58 (m, 2H), 7.72 (m, 1H), 7.88 (m, 1H), 8.13 (m, 1H), 8.21 (m,1H), 8.36 (m, 1H), 8.51 (m, 1H), 8.61 (m, 1H), 10.14 (s, 1H); MassSpectrum: M+H⁺ 403.

TheN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-hydroxypyridine-2-carboxamideused as starting material was prepared from5-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyridine-2-carboxamideaccording to the method used to prepareN-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide from3-{[4-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (methodssection of Example 4).

EXAMPLE 18N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)pyrazine-2-carboxamide

To 2-pyridinylmethanol (300 μL) was added sodium hydride 60% dispersionin oil (20 mg, 1.39 mmol) under inert atmosphere and the mixture stirredat room temperature for 10 minutes. NMP (600 μL) was then added followedby5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-pyrazinecarboxamide(100 mg, 0.303 mmol) and the resulting mixture stirred for 48 hrs. Thesolvent was evaporated under reduced pressure and the residuepartitioned between saturated aqueous sodium bicarbonate and DCM.Evaporation of DCM, precipitation with diethyl ether and isohexanes andfiltration gave the title compound as a solid (25 mg, 20%); NMRSpectrum: (DMSOd₆) 0.58 (m, 2H), 0.69 (m, 2H), 2.31 (s, 3H), 2.86 (m,1H), 5.59 (s, 2H), 7.36 (m, 2H), 7.55 (m, 1H), 7.62 (d, 1H), 7.86 (m,1H), 8.08 (m, 1H), 8.37 (m, 1H), 8.58 (m, 2H), 8.89 (s, 1H), 9.76 (s,1H); Mass Spectrum: M+H⁺ 404.

The5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-pyrazinecarboxamideused as starting material was prepared as follows:—

To 5-hydroxypyrazine-2-carboxylic acid (1 g, 1.14 mmol) was addedphosphorous oxychloride (10 mL) and phosphorous pentachloride (4.91 g).After the initial reaction had subsided the mixture was heated to 100°C. and stirred for 16 h. The mixture was cooled and formic acid (347 mL,9.19 mmol) was added to convert all excess phosphorous pentachloride tophosphorous oxychloride then the excess phosphorous oxychloride wascarefully evaporated off to give a residue which was dissolved in DCM(50 mL). Triethylamine (10 mL) and3-amino-N-cyclopropyl-4-methylbenzamide (1.307 g) were added and theresulting mixture stirred at room temperature for 16 h. The solvent wasevaporated under reduced pressure and the residue purified on a 20 gsilica chromatography column, eluting with 20% methanol/1% ammoniumhydroxide SG 0.88 in ethyl acetate. The crude product was dissolved inDCM and washed with saturated aqueous sodium bicarbonate and evaporatedto dryness to give the title compound as a solid (1.24 g, 52.6%); NMRSpectrum: (DMSOd6) 0.62 (m, 2H), 0.74 (m, 2H), 2.37 (s, 3H), 2.91 (m,1H), 7.41 (m, 1H), 7.70 (m, 1H), 8.05 (m, 1H), 8.44 (m, 1H), 9.02 (m,1H), 9.18 (m, 1H), 10.44 (s, 1H); Mass Spectrum: M−H− 329.

EXAMPLE 19N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-6-(pyridin-2-ylmethoxy)nicotinamide

To 2-pyridinylmethanol (1 mL) was added sodium hydride 60% dispersion inoil (122 mg, 3.05 mmol) under inert atmosphere and the resulting mixturewas stirred for 10 minutes then added to a mixture of6-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}nicotinamide(334 mg, 1.02 mmol) and copper (I) iodide in collidine (3 mL). Theresulting mixture was stirred at room temperature for 30 minutes then at100° C. for 4 h. The mixture was cooled to room temperature, ethylacetate was added and the mixture filtered. The filtrates wereconcentrated under reduced pressure and purified by silica columnchromatography eluting with 0 to 100% ethyl acetate in isohexane.Trituration with diethyl ether gave the title compound as a colourlesssolid (105.6 mg, 26%); NMR Spectrum: (DMSOd₆) 0.59 (m, 2H), 0.67-0.71(m, 2H), 2.27 (s, 3H), 2.86 (m, 1H), 5.53 (s, 2H), 7.10 (d, 1H), 7.35(m, 2H), 7.48 (m, 1H), 7.65 (m, 1H), 7.82 (m, 2H), 8.29 (m, 1H), 8.37(m, 1H), 8.58 (m, 1H), 8.80 (d, 1H), 9.99 (s, 1H); Mass Spectrum: M+H⁺403.

The6-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}nicotinamideused as starting material was prepared as follows:—

To a solution of 6-chloronicotinyl chloride (7.5 g, 42.61 mmol) in DCM(125 mL) cooled in ice was added a mixture of3-amino-N-cyclopropyl-4-methylbenzamide (5 g, 26.31 mmol) andtriethylamine (11.30 mL, 81.07 mmol) in DCM (125 mL). The resultingmixture was stirred for 16 h at room temperature. The mixture wasconcentrated under reduced pressure and the residue partitioned betweenDCM and saturated aqueous potassium carbonate solution. The organicphase was concentrated under reduced pressure and the residue trituratedwith diethyl ether and isohexane and filtered to give the title compoundas a solid (10.56 g); NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H),2.28 (s, 3H), 2.85 (m, 1H), 7.36 (m, 1H), 7.70 (m, 2H), 7.83 (s, 1H),8.38 (m, 2H), 8.98 (s, 1H), 10.24 (s, 1H); Mass Spectrum: M−H− 328.

EXAMPLE 20N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(pyridin-2-ylmethoxy)pyrimidine-5-carboxamide

To a solution of 2-pyridinylmethanol (258 μl, 2.67 mmol) in THF (50 mL)cooled in ice bath to 0° C. was added dropwise lithiumhexamethyldisilazide (1M solution in THF, 2.67 mL, 2.67 mmol) and theresulting mixture stirred for 30 minutes at 0° C.N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamide(1 g, 2.67 mmol) was added and the resulting mixture stirred for 16 h atroom temperature. The reaction mixture was concentrated under reducedpressure and the residue partitioned between water and DCM.Concentration of the organic phase under reduced pressure andcrystallisation from acetonitrile gave the title compound as acolourless solid (132 mg, 12%); NMR Spectrum: (DMSOd₆) 0.57 (m, 2H),0.69 (m, 2H), 2.30 (s, 3H), 2.86 (m, 1H), 5.61 (s, 2H), 7.36 (m, 2H),7.49 (m, 1H), 7.66 (m, 1H), 7.85 (m, 2H), 8.38 (m, 1H), 8.58 (m, 1H),9.16 (s, 2H), 10.16 (s, 1H); Mass Spectrum: M+H⁺ 404.

TheN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamideused as starting material was prepared as follows:—

To a mixture ofN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylthio)pyrimidine-5-carboxamide(3.04 g, 8.82 mmol) in methanol (160 mL) cooled in ice bath to 0° C. wasadded slowly a solution of Oxone® (11.93 g, 19.40 mmol) in water (57 mL)maintaining temperature below 10° C. and the resulting mixture stirredfor 16 hrs at room temperature. The methanol was evaporated and theresidue partitioned between water and ethyl acetate. The organic phasewas washed with brine and concentrated under reduced pressure to givethe title compound as a solid (2.385 g, 72%); NMR Spectrum: (DMSOd₆)0.58 (m, 2H), 0.69 (m, 2H), 2.33 (s, 3H), 2.86 (m, 1H), 3.49 (s, 3H),7.38 (d, 1H), 7.69 (m, 1H), 7.92 (s, 1H), 8.42 (m, 1H), 9.54 (s, 2H),10.56 (s, 1H); Mass Spectrum: M−H⁻ 373.

TheN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylthio)pyrimidine-5-carboxamideused as starting material was prepared as follows:—

To a solution of 2-(methylthio)pyrimidine-5-carboxylic acid (1.50 g,8.82 mmol) and 3-amino-N-cyclopropyl-4-methylbenzamide (1.68 g, 8.82mmol) in DMF (7.5 mL) was added HATU (3.69 g, 9.70 mmol) and DIPEA (4.30mL, 26.46 mmol) and the resulting mixture stirred for 16 h at roomtemperature. Saturated aqueous sodium bicarbonate was added and themixture extracted with ethyl acetate, washed with brine and concentratedunder reduced pressure to give the title compound as a solid (3.04 g,100%); NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H),2.60 (s, 3H), 2.86 (m, 1H), 7.36 (m, 1H), 7.65 (m, 1H), 7.85 (m, 1H),8.39 (m, 1H), 9.12 (s, 2H), 10.18 (m, 1H); Mass Spectrum: M−H′ 341.

The 2-(methylthio)pyrimidine-5-carboxylic acid used as starting materialwas prepared as follows:—

To a solution of ethyl 2-(methylthio)-5-pyrimidinecarboxylate (2.68 g,13.53 mmol) in ethanol (18.6 mL) was added potassium hydroxide (1.304 g,23.28 mmol) and the resulting mixture stirred for 20 minutes at roomtemperature. The solvent was evaporated under reduced pressure and theresidue partitioned between water and diethyl ether. The aqueous phasewas then acidified with dilute aqueous hydrochloric acid and theresulting solid filtered off to give the title compound as a solid (1.96g, 85.2%); NMR Spectrum: (DMSOd₆) 2.58 (m, 3H), 9.01 (s, 2H), 13.54 (m,1H).

The ethyl 2-(methylthio)-5-pyrimidinecarboxylate used as startingmaterial was prepared as follows:—

To a solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (5g, 21.49 mmol) in THF (25 mL) was carefully added zinc powder (4.213 g,64.46 mmol) and the resulting mixture heated to reflux. Glacial aceticacid (1.23 mL, 21.49 mmol) was added and the reaction mixture stirredand heated for 6 h. The mixture was cooled and filtered throughdiatomaceous earth (Celite®) and the filtrate evaporated to dryness togive a solid residue which was triturated with DCM and isohexane. Thefiltrate was evaporated to dryness to give the title compound as a solid(2.68 g, 63%); NMR Spectrum: (DMSOd₆) 1.33 (t, 3H), 2.59 (s, 3H), 4.35(q, 2H), 9.03 (s, 2H).

EXAMPLE 21N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyrimidine-5-carboxamide

A mixture ofN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamide(120 mg, 0.32 mmol), imidazo[1,2-a]pyridine-2-methanol (48 mg, 0.32mmol) and potassium carbonate (44 mg, 0.32 mmol) in THF (5 mL) washeated to 67° C. for 3.5 h. The mixture was cooled to room temperatureand partitioned between DCM and water and the layers separated. Theaqueous layer was extracted with DCM and the combined organic extractsdried (MgSO₄), filtered and concentrated at reduced pressure to give ayellow oil. This material was purified by silica column chromatography,eluting with a gradient of 0 to 8% methanol in DCM to give the titlecompound as a white solid (33 mg, 23%); NMR Spectrum: (DMSOd₆) 0.57 (m,2H), 0.67 (m, 2H), 2.27 (s, 3H), 2.83 (m, 1H), 5.70 (s, 2H), 7.26 (t,1H), 7.35 (d, 1H), 7.66 (m, 2H), 7.78 (d, 1H), 7.83 (d, 1H), 8.30 (s,1H), 8.38 (d, 1H), 8.75 (d, 1H), 9.17 (s, 2H), 10.16 (s, 1H); MassSpectrum: m-H⁻ 441, 443.

The imidazo[1,2-a]pyridine-2-methanol used as starting material wasprepared as follows:—

To a mixture of imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester(500 mg, 2.63 mmol) in THF (10 mL) at 5° C. was added 1M LiAlH₄ in THF(2.63 mL, 2.63 mmol) dropwise under argon. The mixture was stirred at 5°C. for 1 h and then quenched by the addition of ethyl acetate (5 mL) andstirred for a further 15 min. The mixture was partitioned between DCMand water and the layers separated. The organic layer was washed withbrine, dried (MgSO₄), filtered and concentrated at reduced pressure togive a yellow oil. This material was purified by silica columnchromatography, eluting with a gradient of 0 to 10% methanol in DCM togive the title compound as a colourless oil (130 mg, 33%); NMR Spectrum:(CDCl₃); 3.30 (br s, 1H), 4.85 (s, 2H), 6.77 (t, 1H), 7.16 (1H, dt),7.54 (1H, s), 7.57 (1H, s), 8.08 (d, 1H).

EXAMPLE 22N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(1,3-thiazol-4-ylmethoxy)pyrimidine-5-carboxamide

To a solution of thiazole-4-methanol (79 mg) in THF (1 mL) at 0° C.under argon was added 1M lithium bis(trimethylsilyl)amide in THF (0.35mL). After 30 minutesN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamide(127 mg, 0.34 mmol) in THF (3 mL) was added and the reaction warmed toroom temperature and stirred for 5 hours. The reaction mixture waspartitioned between ethyl acetate and water, the organic phases washedwith brine, dried (Na₂SO₄) and concentrated. The residue was purified byflash chromatography on a 12 g silica cartridge eluting with a gradientof 0 to 5% Methanol/DCM to give the title compound as a solid (31 mg,23%); NMR Spectrum: (DMSOd₆) 0.56 (m, 2H), 0.69 (m, 2H), 2.29 (s, 3H),2.85 (m, 1H), 5.63 (s, 2H), 7.36, (d, 1H) 7.67 (dd, 1H), 7.83 (dd, 2H),8.49 (d, 1H), 9.14 (m, 2H), 10.14 (s, 1H); Mass Spectrum: M+H⁺ 410.

The thiazole-4-methanol used as a starting material was prepared asfollows:—

Lithium aluminium hydride (1M solution THF, 1.5 mL) was added slowly toa stirred solution of ethyl thiazole-4-carboxylate (224 mg) in THF (4mL) cooled to 0° C. The reaction mixture was stirred and allowed to warmto room temperature over 1 hour. Ethyl acetate (20 mL) was added to thereaction mixture followed by water (1 mL), 2M NaOH solution (2 mL) thenwater (3 mL). A precipitate formed which was filtered off throughCelite®. The filtrate was concentrated to give the title compound (150mg, 92%); NMR Spectrum: (DMSOd₆) 4.12 (s, 2H), 7.47 (s, 1H), 9.03 (s,1H).

EXAMPLE 23

Using an analogous procedure to that described in Example 22, theappropriate starting material was reacted withN-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamideto give the compounds described in Table 3.

TABLE 3

R⁴ Method Note thiazol-2-ylmethoxy Ex 22 a pyrimidin-2-ylmethoxy Ex 22 b(1-methyl-1H-imidazol-2-yl)methoxy Ex 22 c(1,5-dimethyl-1H-pyrazol-3-yl)methoxy Ex 22 d(1,3-dimethyl-1H-pyrazol-5-yl)methoxy Ex 22 e(3-methylpyridin-2-yl)methoxy Ex 22 f(1-methyl-1H-benzimidazol-2-yl)methoxy Ex 22 g isoquinolin-1-ylmethoxyEx 22 h quinolin-2-ylmethoxy Ex 22 i 1,3-benzothiazol-2-ylmethoxy Ex 22j 1-(2-pyridinyl)ethoxy Ex 22 k Notes a The product gave the followingdata: Mass Spectrum: M + H⁺ 410. b The product gave the following data:NMR Spectrum: (DMSOd₆) 0.50 (m, 2H), 0.61 (m, 2H), 2.23 (s, 3H), 2.50(s, 3H), 2.78 (m, 1H), 3.27 (s, 1H), 5.65 (s, 2H), 7.27 (d, 1H), 7.37(t, 1H), 7.57 (d, 1H), 7.78 (s, 1H), 8.28 (d, 1H), 8.71 (d, 2H), 9.05(s, 1H), 10.07 (s, 1H); Mass Spectrum: M + H⁺ 405. c The product gavethe following data: Mass Spectrum: M + H⁺ 407. d The product gave thefollowing data: Mass Spectrum: M + H⁺ 421. e The product gave thefollowing data: Mass Spectrum: M + H⁺ 421. f The product gave thefollowing data: Mass Spectrum: M + H⁺ 418. g The product gave thefollowing data: Mass Spectrum: M + H⁺ 457. h The product gave thefollowing data: Mass Spectrum: M + H⁺ 454. i The product gave thefollowing data: NMR Spectrum: (DMSOd₆) 0.53 (m, 2H), 0.69 (m, 2H), 2.28(s, 3H), 2.85 (m, 1H), 5.75 (s, 2H), 7.34, (d, 1H) 7.64 (m, 2H), 7.80(m, 1H), 7.64 (s, 1H), 8.01 (d, 2H), 8.38 (s, 1H), 8.43 (d, 1H), 9.15(s, 2H), 10.12 (s, 1H); Mass Spectrum: M + H⁺ 421. j The product gavethe following data: NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H),2.28 (s, 3H), 2.85 (m, 1H), 5.95 (s, 2H), 7.34, (d, 1H) 7.49 (m, 1H),7.55 (m, 1H), 7.66 (m, 1H), 7.85 (s, 1H), 8.03 (d, 1H), 8.14 (d, 1H),8.38 (s, 1H), 9.18 (s, 1H), 10.18 (s, 1H); Mass Spectrum: M − H⁻ 458. kThe product gave the following data: Mass Spectrum: M + H⁺ 418.

EXAMPLE 24N-cyclopropyl-4-methyl-3-{[4-(1-pyridin-2-ylethoxy)benzoyl]amino}benzamide

To 3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (150mg, 0.484 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (937 mg, 1.45 mmol) and the 1-pyridin-2-ylethanol (45 mg,0.363 mmol). Diethyl azodicarboxylate (126 mg, 0.726 mmol) was thenadded dropwise. The reaction was stirred for 17 h at room temperatureand was then filtered and the filtrates were evaporated. The cruderesidue was purified by flash silica chromatography using ethyl acetatein iso-hexane (5-100%) as the eluent to give the title compound as acolourless oil (22 mg, 11%); NMR Spectrum: (DMSOd₆) 0.55 (m, 2H), 0.68(m, 2H), 1.64 (d, 3H), 2.22 (s, 3H), 2.83 (m, 1H), 5.60 (q, 1H), 7.02(d, 2H), 7.31 (d, 2H), 7.43 (d, 1H), 7.62 (d, 1H), 7.80 (m, 2H), 7.90(d, 2H), 8.35 (d, 1H), 8.58 (d, 1H), 9.75 (s, 1H); Mass Spectrum: M+H⁺416.

The 1-pyridin-2-ylethanol used as starting material was prepared asfollows:—To 1-pyridin-2-ylethanone (600 mg, 3.18 mmol) in methanol (10mL) was added polymer supported sodium borohydride (3.0 g, 9.92 mmol)and the reaction was stirred at room temperature for 72 h. The reactionwas filtered and the filtrates were evaporated to give the1-pyridin-2-ylethanol as colourless oil (630 mg, quantitative); NMRSpectrum: (DMSOd₆) 1.38 (d, 3H), 4.71 (q, 1H), 5.30 (br, 1H), 7.21 (m,1H), 7.50 (d, 1H), 7.75 (m, 1H), 8.47 (1H, d); Mass Spectrum: M+H⁺ 192.

EXAMPLE 25N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide

To a solution of methyl6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}methyl)nicotinate(200 mg, 0.436) in THF (10 mL) was added LiAlH₄ (33 mg, 0.871 mmol).Extra THF (7 mL) was added and the mixture was stirred for 16 h at roomtemperature. Glauber's salt (Na₂SO₄.10H₂O) (1.0 g, 3.11 mmol) was addedand the reaction was stirred for a further 16 h. The mixture wasfiltered and the solid washed with methanol (40 mL). The filtrates wereevaporated and the resulting crude material was purified by SCXcartridge to give the title compound as a white solid (150 mg, 80%); NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.67 (m, 2H), 2.25 (s, 3H), 2.85 (m,1H), 4.56 (d, 2H), 5.28 (s, 2H), 5.59 (t, 1H), 7.15 (d, 2H), 7.34 (d,1H), 7.51 (d, 1H), 7.64 (m, 1H), 7.79 (m, 2H), 7.97 (m, 2H), 8.37 (d,1H), 8.55 (s, 1H), 9.83 (s, 1H); Mass Spectrum: M+H⁺ 432.

EXAMPLE 26N-cyclopropyl-3-[(4-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide

To methyl6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}methyl)nicotinate(300 mg, 0.654) in THF (10 mL) at 0° C. was added a 3M solution ofmethyl magnesium bromide in diethyl ether (0.54 mL, 1.62 mmol) dropwiseand the resulting mixture stirred while allowing to warm to ambienttemperature. After 3 h the reaction was at room temperature and a 3Msolution of methyl magnesium bromide in diethyl ether (0.54 mL, 1.62mmol) was added dropwise. The reaction was stirred at room temperaturefor 2 h and then a saturated aqueous solution of ammonium chloride (15mL) was carefully added. The mixture was extracted with DCM (3×20 mL)and the organic layers were combined, filtered and the filtratesevaporated. The resulting crude product was purified by silica flashchromatography using ethyl acetate as the eluent to give a mixture ofthe product and the corresponding methyl ketone. This was dissolved inDCM (5 mL) and polymer supported tosyl hydrazine (400 mg, 1.07 mmol) andacetic acid (1 drop) were added. After stirring for 16 h at roomtemperature the reaction had MP carbonate (275 mg, 0.751 mmol) added andwas stirred for 30 minutes at room temperature. The mixture was filteredand the solid washed with methanol. The filtrates and washings werecombined and evaporated to give the title compound as a white solid (65mg, 22%); NMR Spectrum: (DMSOd₆) 0.62 (m, 2H), 0.74 (m, 2H), 1.52 (s,6H), 2.31 (s, 3H), 2.90 (m, 1H), 5.61 (s, 2H), 7.21 (d, 2H), 7.38 (d,1H), 7.52 (d, 1H), 7.19 (d, 1H), 7.86 (s, 1H), 7.94 (m, 1H), 8.02 (d,2H), 8.41 (d, 1H), 8.76 (d, 1H), 9.88 (s, 1H); Mass Spectrum: M+H⁺ 460.

EXAMPLE 27N-cyclopropyl-3-{[4-({5-[(dimethylamino)methyl]pyridin-2-yl}methoxy)benzoyl]amino}-4-methylbenzamide

ToN-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide(100 mg, 0.232 mmol) in DCM (10 mL) was added Dess-Martin periodinane(197 mg, 0.464 mmol) and the reaction was stirred at room temperaturefor 3 h. The reaction was diluted with DCM (40 mL), washed with 2N NaOH(3×15 mL) and then a saturated brine solution (20 mL). The DCM solutionof the aldehyde was dried with magnesium sulphate and then concentratedunder reduced pressure to approximately 10 mL. To this solution wasadded dimethylamine (2M in THF, 0.13 mL, 0.260 mmol), acetic acid (2drops) and titanium iso-propoxide (132 mg, 0.464 mmol). The mixture wasstirred at room temperature for 1 h and then sodiumtriacetoxyborohydride (123 mg, 0.580 mmol) was added. The reaction wasstirred for 18 h at room temperature. Water (4 drops) was added and thereaction was evaporated to dryness. The residue was purified by basicpreparative HPLC to give the title compound as a white solid (30 mg,28%); NMR Spectrum: (DMSOd₆) 0.62 (m, 2H), 0.75 (m, 2H), 2.21 (s, 6H),2.31 (s, 3H), 2.90 (m, 1H), 3.48 (s, 2H), 5.83 (s, 2H), 7.22 (d, 2H),7.38 (d, 1H), 7.57 (d, 1H), 7.68 (dd, 1H), 7.81 (m, 1H), 7.85 (d, 1H),8.04 (d, 2H), 8.42 (d, 1H), 8.57 (s, 1H), 9.88 (s, 1H); Mass Spectrum:M+H⁺ 459.

EXAMPLE 28N-cyclopropyl-3-{[4-({5-[(isopropylamino)methyl]pyridin-2-yl}methoxy)benzoyl]amino}-4-methylbenzamide

Using an analogous procedure to that described in Example 27,N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamidewas oxidised and the resulting aldehyde reacted with isopropylamine togive the title compound; NMR Spectrum: (DMSOd₆) 0.58 (m, 2H), 0.68 (m,2H), 1.00 (d, 6H), 2.25 (s, 3H), 2.70 (m, 1H), 2.86 (m, 1H), 3.71 (s,2H), 5.76 (s, 2H), 7.14 (d, 2H), 7.33 (d, 1H), 7.49 (d, 1H), 7.64 (m,1H), 7.80 (m, 2H), 7.99 (d, 2H), 8.40 (d, 1H), 8.55 (s, 1H), 9.87 (s,1H); Mass Spectrum: M+H⁺ 473.

EXAMPLE 29N-cyclopropyl-3-[(4-{[6-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide

3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (100 mg,0.323 mmol), [6-(bromomethyl)pyridin-2-yl]methanol (71 mg, 0.355 mmol)and potassium carbonate (49 mg, 0.355 mmol) were mixed in acetonitrile(3 mL) and the reaction was stirred at room temperature for 16 h. Thereaction was then heated at 100° C. in the microwave for 10 mins. Water(10 mL) was added and the mixture was extracted with DCM (3×15 mL). Theorganic layers were combined and evaporated to give a white solid whichwas triturated with DCM to give the title compound as a white solid (80mg, 58%); NMR Spectrum: (DMSOd₆) 0.58 (m, 2H), 0.68 (m, 2H), 2.25 (s,3H), 2.85 (m, 1H), 4.59 (s, 2H), 5.24 (s, 2H), 7.16 (d, 2H), 7.32 (d,1H), 7.38 (d, 1H), 7.45 (d, 1H), 7.63 (m, 1H), 7.80 (m, 2H), 7.97 (d,2H), 8.36 (d, 1H), 9.82 (s, 1H); Mass Spectrum: M+H⁺ 432.

EXAMPLE 30 Methyl6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}methyl)pyridine-2-carboxylate

3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (200 mg,0.626 mmol), pyridine (164 mg, 0.710 mmol) and potassium carbonate (98mg, 0.710 mmol) were mixed in acetonitrile (6 mL) and the reaction wasstirred at room temperature for 16 h. The reaction was then heated at100° C. in the microwave for 20 mins. Water (10 mL) was added and themixture was extracted with DCM (3×20 mL). The organic layers werecombined and evaporated to give a white solid which was triturated withDCM to give the title compound as a white solid (220 mg, 74%); NMRSpectrum: (DMSOd₆) 0.58 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.85 (m,1H), 3.92 (s, 3H), 5.37 (s, 2H), 7.19 (d, 2H), 7.32 (d, 1H), 7.63 (m,1H), 7.80 (m, 2H), 8.05 (m, 4H), 8.38 (d, 1H), 9.85 (s, 1H); MassSpectrum: M+H⁺ 460.

EXAMPLE 31N-cyclopropyl-3-[(4-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide

To methyl6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}methyl)pyridine-2-carboxylate(139 mg, 0.303-mmol) in THF (5 mL) at 0° C. was added a 3M solution ofmethyl magnesium bromide in diethyl ether (0.44 mL, 1.32 mmol) dropwise.The mixture was stirred in the melting ice bath. After 3 h the reactionwas at room temperature and a 3M solution of methyl magnesium bromide indiethyl ether (0.50 mL, 1.50 mmol) was added dropwise. The reaction wasstirred at room temperature for 72 h and then a saturated aqueoussolution of ammonium chloride (15 mL) was carefully added. The mixturewas extracted with DCM (3×20 mL) and the organic layers were combined,filtered and the filtrates were evaporated. This crude solid wasdissolved in DCM (5 mL) and polymer supported tosyl hydrazine (100 mg,0.268 mmol) and acetic acid (2 drops) were added and the mixture wasstirred for 1 h. The reaction was filtered and the solid washed withmethanol (10 mL) and the filtrates and washings were combined andevaporated to dryness. The resulting crude product was purified bysilica flash chromatography using ethyl acetate in iso-hexane (50 to100%) as the eluent to give the title compound as a white solid (47 mg,34%); NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 1.46 (s, 6H),2.25 (s, 3H), 2.85 (m, 1H), 5.27 (s, 2H), 7.17 (d, 2H), 7.32 (d, 1H),7.38 (d, 1H), 7.62 (m, 2H), 7.81 (m, 2H), 7.97 (d, 2H), 8.35 (d, 1H),9.81 (s, 1H); Mass Spectrum: M+H⁺ 460.

EXAMPLE 32N-cyclopropyl-3-({4-[(6-{[2-(diethylamino)ethoxy]methyl}pyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide

To a 60% dispersion of NaH in mineral oil (25 mg, 0.625 mmol) in DMA (4mL) was added N,N-diethylethanolamine (24 mg, 0.205 mmol). The reactionwas stirred at room temperature for 20 minutes. A solution of3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl-4-methylbenzamide(77 mg, 0.155 mmol) in DMA (2 mL) was added dropwise to the reactionwhich was then stirred for 1 h at room temperature. The reaction wasquenched by the addition of water (1 mL) and was purified by preparativeHPLC to give the title compound as a white solid (29 mg, 35%); NMRSpectrum: (DMSOd₆) 0.58 (m, 2H), 0.69 (m, 2H), 0.96 (t, 6H), 2.26 (s,3H), 2.50 (m, 4H), 2.64 (t, 2H), 2.86 (m, 1H), 3.59 (t, 2H), 4.59 (s,2H), 5.75 (s, 2H), 7.18 (d, 2H), 7.33 (d, 1H), 7.42 (m, 2H), 7.64 (dd,1H), 7.80 (s, 1H), 7.87 (t, 1H), 7.96 (d, 2H), 8.36 (d, 1H), 9.83 (s,1H); Mass Spectrum: M+H⁺ 531.

The3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl-4-methylbenzamideused as starting material was prepared as follows:—

To 3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (1.50g, 4.84 mmol) and potassium carbonate (3.34 g, 24.2 mmol) in refluxingacetonitrile (20 mL) was added a solution of2,6-bis(bromomethyl)pyridine (5.13 g, 19.4 mmol) in acetonitrile (10 mL)over 25 mins. The reaction was cooled to room temperature and water (20mL) was added. The mixture was extracted with DCM (3×30 mL) and theorganic layers were combine and evaporated to leave a solid which wastriturated with hot ethyl acetate to give3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl-4-methylbenzamideas a white solid (1.449 g, 61%); NMR Spectrum: (DMSOd₆) 0.58 (m, 2H),0.70 (m, 2H), 2.27 (s, 3H), 2.85 (m, 1H), 4.73 (s, 2H), 5.30 (s, 2H),7.19 (d, 2H), 7.32 (d, 1H), 7.49 (d, 1H), 7.55 (d, 1H), 7.65 (d, 1H),7.81 (s, 1H), 7.90 (t, 1H) 7.98 (d, 2H), 8.38 (d, 1H), 9.85 (s, 1H);Mass Spectrum: M+H⁺ 494, 496 Br pattern.

EXAMPLE 33N-cyclopropyl-3-({4-[(6-{[2-(dimethylamino)ethoxy]methyl}pyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide

Using an analogous procedure to that described in Example 32,2-dimethylaminoethanol was reacted with3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl-4-methylbenzamideto give the title compound; NMR Spectrum: (DMSOd₆) 0.58 (m, 2H), 0.69(m, 2H), 2.19 (s, 6H), 2.26 (s, 3H), 2.50 (m, 2H), 2.86 (m, 1H), 3.62(t, 2H), 4.60 (s, 2H), 5.28 (s, 2H), 7.18 (d, 2H), 7.34 (d, 1H), 7.41(d, 1H), 7.46 (d, 1H), 7.63 (d, 1H), 7.80 (s, 1H), 7.89 (t, 1H), 7.98(d, 2H), 8.37 (d, 1H), 9.83 (s, 1H); Mass Spectrum: M+H⁺ 503.

EXAMPLE 34N-cyclopropyl-3-{[4-({6-[(2-methoxyethyl)amino]pyridin-2-yl}methoxy)benzoyl]amino}-4-methylbenzamide

A mixture ofN-cyclopropyl-4-methyl-3-({4-[(6-bromo-2-pyridinyl)methoxy]benzoyl}amino)benzamide(100 mg, 0.21 mmol), 2-methoxyethylamine (500 μL) and NMP (500 μL) washeated to 190° C. in the microwave for 90 min. The cooled reactionmixture was eluted through a silica cartridge with isohexane then ethylacetate to give the crude product which was triturated with diethylether to give the title compound as a solid (36 mg); NMR Spectrum:(DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.27 (s, 3H), 2.85 (m, 1H), 3.28(m, 2H), 3.31 (m, 3H), 5.08 (s, 2H), 6.47 (d, 1H), 6.61 (d, 2H), 7.14(d, 2H), 7.32 (m, 2H), 7.40 (m, 1H), 7.63 (m, 1H), 7.80 (m, 2H), 7.97(m, 2H), 8.37 (m, 1H), 9.84 (s, 1H); Mass Spectrum: M+H⁺ 475.

EXAMPLE 35N-cyclopropyl-3-({4-[(6-{[2-(dimethylamino)ethyl]amino}pyridin-2-yl)methoxy]benzoyl}amino)-4-methylbenzamide

Using an analogous procedure to that described in Example 34,2-dimethylaminoethylamine was reacted withN-cyclopropyl-4-methyl-3-({4-[(6-bromo-2-pyridinyl)methoxy]benzoyl}amino)benzamideto give the title compound; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.69(m, 2H), 2.16 (s, 2H), 2.22 (s, 6H), 2.27 (s, 3H), 2.43 (t, 2H), 2.86(m, 1H), 5.07 (s, 2H), 6.38 (t, 1H), 6.44 (d, 1H), 6.60 (d, 1H), 7.13(d, 2H), 7.63 (m, 1H), 7.82 (s, 1H), 7.97 (d, 2H), 8.36 (m, 1H), 9.83(s, 1H); Mass Spectrum: M+H⁺ 488.

EXAMPLE 36N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amino)benzamidehydrochloride

To a solution ofN-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amino)benzamide(20 mg, 0.05 mmol) in 1:1 DCM and methanol (2.0 mL) was addedhydrochloric acid (0.05 mmol). The solvent was evaporated to give thetitle compound; NMR Spectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.26(s, 3H), 2.44 (s, 3H), 2.85 (m, 1H), 5.25 (s, 2H), 6.37 (s, 1H), 7.15(m, 2H), 7.31 (m, 1H), 7.61 (m, 1H), 7.78 (s, 1H), 7.98 (m, 2H), 8.37(s, 1H), 9.82 (s, 1H); Mass Spectrum: M−H⁻ 404, M+Na⁺ 428.

EXAMPLE 37N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amino)benzamidehydrobromide

Using an analogous procedure to that described in Example 36,N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amino)benzamidewas reacted with hydrobromic acid to give the title compound; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.44 (s,3H), 2.85 (m, 1H), 5.25 (s, 2H), 6.37 (s, 1H), 7.15 (m, 2H), 7.31 (m,1H), 7.61 (m, 1H), 7.78 (s, 1H), 7.98 (m, 2H), 8.37 (s, 1H), 9.82 (s,1H); Mass Spectrum: M−⁻ 404, M+Na⁺ 428.

EXAMPLE 38N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amino)benzamidemethanesulfonate

Using an analogous procedure to that described in Example 36,N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amino)benzamidewas reacted with methanesulfonic acid to give the title compound: NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.44 (s,3H), 2.52 (s, 3H), 2.85 (m, 1H), 5.25 (s, 2H), 6.37 (s, 1H), 7.15 (m,2H), 7.31 (m, 1H), 7.61 (m, 1H), 7.78 (s, 1H), 7.98 (m, 2H), 8.37 (s,1H), 9.82 (s, 1H), 12.12 (br s, 1H); Mass Spectrum: M−H⁻ 404, M+Na⁺ 428.

EXAMPLE 39N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamidehydrochloride

Using an analogous procedure to that described in Example 36,N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamidewas reacted with hydrochloric acid to give the title compound; NMRSpectrum: (DMSOd₆) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s, 3H), 2.86 (m,1H), 5.44 (s, 2H), 7.18 (d, 2H), 7.32 (m, 1H), 7.65 (m, 2H), 7.81 (m,2H), 7.98 (d, 2H), 8.19 (m, 1H), 8.36 (m, 1H), 8.73 (m, 1H), 9.85 (s,1H); Mass Spectrum: M+H⁺ 401.

EXAMPLE 40N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamidesulfate

Using an analogous procedure to that described in Example 36,N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamidewas reacted with sulfonic acid to give the title compound; NMR Spectrum:(DMSOd₆) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s, 3H), 2.86 (m, 1H), 5.46(s, 2H), 7.18 (d, 2H), 7.32 (m, 1H), 7.62 (m, 1H), 7.75 (m, 2H), 7.89(m, 1H), 7.99 (d, 2H), 8.36 (m, 2H), 8.80 (m, 1H), 9.85 (s, 1H); MassSpectrum: M+H⁺ 401.

EXAMPLE 41N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-ylmethoxy)benzamidehydrochloride

Using an analogous procedure to that described in Example 36,N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-ylmethoxy)benzamidewas reacted with hydrochloric acid to give the title compound; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.28 (s, 3H), 2.86 (m,1H), 5.60 (s, 2H), 7.32 (m, 1H), 7.43 (m, 1H), 7.66 (m, 1H), 7.84 (m,5H), 8.40 (m, 2H), 8.83 (m, 1H), 10.07 (br s, 1H); Mass Spectrum: M+H⁺420.

EXAMPLE 42N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-ylmethoxy)benzamidehydrobromide

Using an analogous procedure to that described in Example 36,N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-ylmethoxy)benzamidewas reacted with hydrobromic acid to give the title compound; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.25 (s, 3H), 2.86 (m,1H), 5.48 (s, 2H), 7.32 (m, 1H), 7.42 (m, 1H), 7.64 (m, 2H), 7.82 (m,4H), 8.17 (m, 1H), 8.37 (m, 1H), 8.75 (m, 1H), 9.92 (s, 1H); MassSpectrum: M+H⁺ 420.

EXAMPLE 43N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-ylmethoxy)benzamidemethanesulfonate

Using an analogous procedure to that described in Example 36,N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-ylmethoxy)benzamidewas reacted with methanesulfonic acid to give the title compound; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.68 (m, 2H), 2.25 (s, 3H), 2.40 (s,3H), 2.86 (m, 1H), 5.51 (s, 2H), 7.32 (m, 1H), 7.42 (m, 1H), 7.63 (m,1H), 7.73 (m, 1H), 7.78 (s, 1H), 7.86 (m, 3H), 8.25 (m, 1H), 8.37 (m,1H), 8.78 (m, 1H), 9.95 (s, 1H); Mass Spectrum: M+H⁺ 420.

EXAMPLE 442-(1,3-benzothiazol-2-ylmethoxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyrimidine-5-carboxamidehydrobromide

Using an analogous procedure to that described in Example 36,2-(1,3-benzothiazol-2-ylmethoxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyrimidine-5-carboxamidewas reacted with hydrobromic acid to give the title compound; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.85 (m,1H), 5.10 (s, 2H), 7.34, (d, 1H) 7.49 (m, 1H), 7.55 (m, 1H), 7.66 (m,1H), 7.76 (s, 1H), 7.99 (d, 1H), 8.10 (d, 1H), 8.38 (s, 1H), 9.11 (s,2H), 9.19, (s, 1H), 10.09 (s, 1H); Mass Spectrum: M−H⁻ 458.

EXAMPLE 452-(1,3-benzothiazol-2-ylmethoxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyrimidine-5-carboxamidemethanesulfonate

Using an analogous procedure to that described in Example 36,2-(1,3-benzothiazol-2-ylmethoxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyrimidine-5-carboxamidewas reacted with methanesulfonic acid to give the title compound; NMRSpectrum: (DMSOd₆) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.52 (s,3H), 2.85 (m, 1H), 5.91 (s, 2H), 7.34, (d, 1H) 7.49 (m, 1H), 7.55 (m,1H), 7.66 (m, 1H), 7.76 (s, 1H), 7.99 (d, 1H), 8.10 (d, 1H), 8.38 (s,1H), 9.11 (s, 2H), 9.17, (s, 1H), 10.17 (s, 1H), 10.78 (br s, 1H); MassSpectrum: M−H⁻ 458.

EXAMPLE 46N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)pyridine-2-carboxamidehydrobromide

Using an analogous procedure to that described in Example 36,N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)pyridine-2-carboxamidewas reacted with hydrobromic acid to give the title compound; NMRSpectrum: (DMSOd₆) 0.58 (m, 2H), 0.69 (m, 2H), 2.32 (s, 3H), 2.86 (m,1H), 5.49 (s, 2H), 7.33 (m, 1H), 7.58 (m, 1H), 7.76 (m, 2H), 7.95 (m,1H), 8.15 (m, 2H), 8.34 (m, 2H), 8.53 (m, 1H), 8.82 (m, 1H), 10.13 (s,1H); Mass Spectrum: M+H⁺ 403.

The invention claimed is:
 1. A compound of the Formula. I

wherein Q_(a) is phenyl or heteroaryl, and Q_(a) may optionally bear 1or 2 substituents selected from hydroxy, halogeno, trifluoromethyl,cyano, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl; R₁ andR₂ are each independently selected from hydrogen, (1-6C)alkyl,(2-6C)alkenyl and (2-6C)alkynyl; and Q_(b) is phenyl, heteroaryl orheterocyclyl, and Q_(b) may optionally bear 1 or 2 substituents selectedfrom hydroxy, halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,(3-6C)cycloalkoxy, (3-6C)cycloalkcyl-(1-6C)alkoxy, carboxy,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,aminosulphonyl, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyland (3-6C)cycloalkylsulphonyl; and wherein any of the substituents onQ_(a) or Q_(b) defined hereinbefore which comprise a CH₂ group which isattached to 2 carbon atoms or a CH₃ group which is attached to a carbonatom may optionally bear on each said CH₂ or CH₃ group one or moresubstituents selected from hydroxy, cyano, amino, (1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; or apharmaceutically-acceptable salt thereof.
 2. A compound of the Formula Iaccording to claim 1 wherein Q_(a) is phenyl, pyridyl, pyrimidinyl,pyrazinyl or pyridazinyl, and Q_(a) may optionally bear 1 or 2substituents selected from halogeno, (1-6C)alkyl and (1-6C)alkoxy; R₁and R₂ are each independently selected from hydrogen, (1-6C)alkyl,(2-6C)alkenyl and (2-6C)alkynyl; and Q_(b) is phenyl, heteroaryl orheterocyclyl, and Q_(b) may optionally bear 1 or 2 substituents selectedfrom hydroxy, halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,(3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,aminosulphonyl, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyland (3-6C)cycloalkylsulphonyl; and wherein any of the substituents onQ_(a) or Q_(b) defined hereinbefore which comprise a CH₂ group which isattached to 2 carbon atoms or a CH₃ group which is attached to a carbonatom may optionally bear on each said CH₂ or CH₃ group one or moresubstituents selected from hydroxy, cyano, amino, (1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; or apharmaceutically-acceptable salt thereof.
 3. A compound of the Formula Iaccording to claim 1 or claim 2 wherein Q_(a) is phenyl, pyridyl,pyrimidinyl, pyrazinyl or pyridazinyl, and Q_(a) may optionally bear 1or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl and(1-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
 4. Acompound of the Formula I according to claim 1 or claim 2 wherein Q_(b)is phenyl or heteroaryl, and Q_(b) may optionally bear 1 or 2substituents selected from hydroxy, halogeno, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, aminosulphonyl,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl and(3-6C)cycloalkylsulphonyl; and wherein any of the substituents on Q_(b)which comprise a CH₂ group which is attached to 2 carbon atoms or a CH₃group which is attached to a carbon atom may optionally bear on eachsaid CH₂ or CH₃ group one or more substituents selected from hydroxy,cyano, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino; or a pharmaceutically-acceptable salt thereof. 5.A compound of the Formula I according to claim 1 or claim 2 whereinQ_(b) is phenyl, pyridyl, pyrazinyl, pyridazinyl, thiazolyl,thiadiazolyl, imidazolyl, isoxazolyl, oxazolyl, furanyl, thienyl,benzimidazolyl, isoquinolinyl, quinolinyl, benzothiazolyl orpyrido[1,2-a]imidazolyl, and Q_(b) may optionally bear 1 or 2substituents selected from hydroxy, halogeno, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, aminosulphonyl,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl and(3-6C)cycloalkylsulphonyl; and wherein any of the substituents on Q_(b)which comprise a CH₂ group which is attached to 2 carbon atoms or a CH₃group which is attached to a carbon atom may optionally bear on eachsaid CH₂ or CH₃ group one or more substituents selected from hydroxy,cyano, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino; or a pharmaceutically-acceptable salt thereof. 6.A compound of the Formula I according to claim 1 or claim 2 wherein R₁and R₂ are each independently selected from hydrogen, (1-6C)alkyl,(2-6C)alkenyl and (2-6C)alkynyl; or a pharmaceutically-acceptable saltthereof.
 7. A compound of the Formula I according to claim 1 or claim 2wherein R₁ and R₂ are each independently selected from hydrogen and(1-6C)alkyl; or a pharmaceutically-acceptable salt thereof.
 8. Acompound of the Formula I according to claim 1 wherein Q_(a) is phenyl,pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, and Q_(a) may optionallybear 1 or 2 substituents selected from halogeno, (1-6C)alkyl and(1-6C)alkoxy; R₁ and R₂ are each independently selected from hydrogenand (1-6C)alkyl; and Q_(b) is phenyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, thiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, oxazolyl,furanyl, thienyl, benzimidazolyl, isoquinolinyl, quinolinyl,benzothiazolyl or pyrido[1,2-a]imidazolyl, and Q_(b) may optionally bear1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,amino, (1-6C)alkylamino, di-[(-6C)alkyl]amino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, aminosulphonyl,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl and(3-6C)cycloalkylsulphonyl; and wherein any of the substituents on Q_(b)which comprise a CH₂ group which is attached to 2 carbon atoms or a CH₃group which is attached to a carbon atom may optionally bear on eachsaid CH₂ or CH₃ group one or more substituents selected from hydroxy,cyano, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino; or a pharmaceutically-acceptable salt thereof. 9.A process for preparing a compound of the Formula I, orpharmaceutically-acceptable salt thereof which comprises: (a) reacting abenzoic acid of the Formula II, or a activated derivative thereof,

with an amine of the Formula III

under standard amide bond forming conditions, wherein Q_(a), Q_(b), R₁and R₂ are as defined in claim 1 or claim 2 and wherein any functionalgroup is optionally protected, and: (i) removing any protecting groups;and (ii) optionally forming a pharmaceutically-acceptable salt; or (b)reacting an acid of the Formula IV, or an activated derivative thereof,

with an aniline of the Formula VI

under standard amide bond forming, wherein Q_(a), Q_(b), R₁ and R₂ areas defined in claim 1 or claim 2 and wherein any functional group isoptionally protected, and: (i) removing any protecting groups; (ii)optionally forming a pharmaceutically-acceptable salt; or (c) for thepreparation of a compound of the Formula I wherein a substituent onQ_(a) or Q_(b) is (1-6C)alkoxy or substituted (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino or substituted (1-6C)alkylamino,the alkylation of an amide derivative of the Formula I wherein asubstituent on Q_(a) or Q_(b) is hydroxy or amino.